ALK7 binding proteins and uses thereof

ABSTRACT

This disclosure provides ALK7-binding proteins such as anti-ALK7 antibodies, and compositions and methods for making the ALK7-binding proteins. In certain embodiments the ALK7-binding proteins inhibit, or antagonize ALK7 activity. In addition, the disclosure provides compositions and methods for diagnosing and treating overweight, obesity, diabetes, overweight, obesity, type 2 diabetes, and their associated conditions; metabolic disorders, and other diseases or conditions that can be treated, prevented or ameliorated by targeting ALK7.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.15/494,081, filed Apr. 21, 2017, which claims the benefit of U.S.Provisional Appl. No. 62/326,313, filed Apr. 22, 2016, each of which isincorporated herein by reference.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

The content of the electronically submitted sequence listing in ASCIItext file 3174.004PC01_SeqList.ST25txt (Size: 72,898 bytes; and Date ofCreation: Apr. 21, 2017) filed with the application is hereinincorporated by reference in its entirety.

BACKGROUND

Overweight and obesity have reached epidemic proportion in the UnitedStates and a number of countries throughout the world, increasing amongall age, race and ethnic groups and in both men and women. Overweightand obesity are also associated with other diseases or conditions thatdisrupt life activities and lifestyles. Obesity is recognized as aserious risk factor for other diseases and conditions such as type 2diabetes, inflammation, and cardiovascular, pulmonary, fatty liverdisease, neurologic, and hepatic, and renal disease.

Type 2 diabetes is a chronic, progressive disease that has likewisereached epidemic proportion. There is no established cure for type IIdiabetes, but there are numerous recognized treatments that attempt todelay or mitigate the inevitable consequences of the disease. Type 2diabetes is initially treated by adjustments in diet and exercise, andby weight loss, most especially in obese subjects. The amount of weightloss which improves the clinical picture is sometimes modest (e.g., 4.4to 11 lbs.); this is likely due to poorly understood aspects of fattissue activity, for instance chemical signaling (especially in visceralfat tissue in and around abdominal organs).

In view of the foregoing, there is a need for new treatments forcontrolling and treating the overweight, obesity and type 2 diabetesepidemics. It is an object of this disclosure to provide ALK7-bindingproteins and uses of the same in the diagnosis and treatment, preventionand/or amelioration of overweight, obesity, type 2 diabetes, and theirassociated conditions; metabolic disorders, and other diseases orconditions that can be treated, prevented or ameliorated by targetingALK7.

BRIEF SUMMARY

The disclosure provides ALK7-binding proteins and methods of using theALK7-binding proteins. In particular embodiments, the ALK7-bindingproteins are capable of inhibiting or blocking the binding of ALK7 toone or more cognate ALK7 ligands and/or one or more cognate ActRIreceptors. In some embodiments, the ALK7-binding proteins are capable ofinhibiting or blocking the multimerization of ALK7, and ActRII receptor(ActRIIA or ActRIIB) and GDF1, GDF3, GDF8, activin B, activin A/B, orNodal. The disclosure also provides methods of using ALK7-bindingproteins for the diagnosis, or treatment, prevention and/or ameliorationof a disease or condition associated with ALK7 expression and/orelevated ALK7-mediated signaling. Such diseases or conditions includebut are not limited to, overweight, obesity (e.g., abdominal obesity);insulin resistance; metabolic syndrome and other metabolic diseases orconditions; a lipid disorder such as, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia or dyslipidemia; lipoproteinaberrations; decreased triglycerides; inflammation (e.g., liverinflammation and/or inflammation of adipose tissue), fatty liverdisease; non-alcoholic fatty liver disease; hyperglycemia; impairedglucose tolerance (IGT); hyperinsulinemia; high cholesterol (e.g., highLDL levels and hypercholesterolemia); cardiovascular disease such as,heart disease including coronary heart disease, congestive heartfailure, stroke, peripheral vascular disease, disordered fibrinolysis,atherosclerosis; arteriosclerosis, and hypertension; Syndrome X;vascular restenosis; neuropathy; retinopathy; neurodegenerative disease;endothelial dysfunction, respiratory dysfunction, renal disease (e.g.,nephropathy); pancreatitis; polycystic ovarian syndrome; elevated uricacid levels; haemochromatosis (iron overload); acanthosis nigricans(dark patches on the skin); and cancer (e.g., myeloma (e.g., multiplemyeloma, plasmacytoma, localized myeloma, or extramedullary myeloma), oran ovarian, breast, colon, endometrial, liver, kidney, pancreatic,gastric, uterine or colon cancer); and other disorders/conditionsassociated with one or more of the above diseases or conditions, or withexcessive body weight (e.g., body mass index (BMI)≥25 kg/m²), or toomuch body fat. The disclosure also provides without limitation, methodsfor reducing body weight (e.g., promoting weight loss), and methods forreducing weight gain (e.g., preventing weight gain), using antagonistALK7-binding proteins, such as antibodies.

In some embodiments, the ALK7-binding protein specifically binds ALK7.In further embodiments, the provided ALK7-binding protein specificallybinds ALK7 and has at least one characteristic selected from the groupconsisting of: (a) decreases the formation of a complex containing ALK7,a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with ActRIIA or ActRIIB) for binding to ALK7; (c)competes with one or more TGF-beta superfamily ligands (e.g., activin B,activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding to ALK7; (d)decreases the phosphorylation of ALK7 in cells expressing ALK7 and atype II receptor (e.g., ActRIIA or ActRIIB) in the presence of one ormore TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activin B,activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.In further embodiments, the ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody having an ALK7-binding VHand VL pair disclosed herein. In further embodiments, the ALK7-bindingprotein is an anti-ALK7 antibody or an ALK7-binding antibody fragment.

In some embodiments, the ALK7-binding protein comprises a set ofcomplementary determining regions (CDRs): heavy chain variable region(VH)-CDR1, VH-CDR2, VH-CDR3, light chain variable region (VL)-CDR1,VL-CDR2 and VL-CDR3, wherein the CDRs are present in a heavy chainvariable region (VH) and a light chain variable region (VL) pairdisclosed in Table 1A. In some embodiments, the ALK7-binding proteincomprises a set of CDRs present in a VH and a VL pair selected from thegroup consisting of: (a) a VH sequence of SEQ ID NO:4, and a VL sequenceof SEQ ID NO:13; (b) a VII sequence of SEQ ID NO:22, and a VL sequenceof SEQ ID NO:31; (c) a VH sequence of SEQ ID NO:40, and a VL sequence ofSEQ ID NO:49; and (d) a VH sequence of SEQ ID NO:58 and a VL sequence ofSEQ ID NO:67.

In some embodiments, the ALK7-binding protein comprises a set ofcomplementary determining regions (CDRs): heavy chain variable region(VH)-CDR1, VH-CDR2, VH-CDR3, light chain variable region (VL)-CDR1,VL-CDR2 and VL-CDR3, wherein the CDRs are present in a heavy chainvariable region (VH) and a light chain variable region (VL) pairdisclosed in Table 1B or Table 3. In some embodiments, the ALK7-bindingprotein comprises a set of CDRs present in a VH and a VL pair selectedfrom the group consisting of: (a) a VII sequence of SEQ ID NO: 152, anda VL sequence of SEQ ID NO:98; (b) a VII sequence of SEQ ID NO:159, anda VL sequence of SEQ ID NO:110; and (c) a VII sequence of SEQ ID NO:165,and a VL sequence of SEQ ID NO:171. In some embodiments, theALK7-binding protein comprises a set of CDRs present in a VH and a VLpair selected from the group consisting of: (a) a VH sequence of SEQ IDNO:91, and a VL sequence of SEQ ID NO:98; (b) a VH sequence of SEQ IDNO: 105, and a VL sequence of SEQ ID NO:110; (c) a VH sequence of SEQ IDNO:117, and a VL sequence of SEQ ID NO:124; (d) a VH sequence of SEQ IDNO:128 and a VL sequence of SEQ ID NO:135; and (e) a VH sequence of SEQID NO:140 and a VL sequence of SEQ ID NO:148.

In additional embodiments, the ALK7-binding protein specifically bindsALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1,VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to, or has atotal of one, two, three, four, five, six, seven, eight, nine, ten, orfewer than ten, amino acid substitutions, deletions, and/or insertionsfrom a reference set of CDRs in which: (a)(i) VH-CDR1 comprises theamino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the aminoacid sequence of SEQ ID NO:2; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:3; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO: 10; (v) VL-CDR2 comprises the amino acid sequence of SEQID NO: 11; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO: 12; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:19; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:21; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO:28; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:29; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:30; (c)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:38; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:39; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:46; (v) VL-CDR2 comprisesthe amino acid sequence of SEQ ID NO:47: and (vi) VL-CDR3 comprises theamino acid sequence of SEQ ID NO:48; or (d)(i) VH-CDR1 comprises theamino acid sequence of SEQ ID NO:55; (ii) VH-CDR2 comprises the aminoacid sequence of SEQ ID NO:56; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:57; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO:64; (v) VL-CDR2 comprises the amino acid sequence of SEQ IDNO:65; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO:66; and wherein the protein binds ALK7.

In additional embodiments, the ALK7-binding protein specifically bindsALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1,VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to, or has atotal of one, two, three, four, five, six, seven, eight, nine, ten, orfewer than ten, amino acid substitutions, deletions, and/or insertionsfrom a reference set of CDRs in which: (a)(i) VH-CDR1 comprises theamino acid sequence of SEQ ID NO:88; (ii) VH-CDR2 comprises the aminoacid sequence of SEQ ID NO:89; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:90; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ IDNO:96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO:97; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:103;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 104; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO:107; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:108; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:109; (c)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:114; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:115; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:116; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:121; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:122; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:123; (d)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:125; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:126; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:127; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:132; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO: 133; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:134; or (e)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:138; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:139; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:145; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:146; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:147; and wherein theprotein binds ALK7.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs in which: (a)(i) VH-CDR1 comprises the aminoacid sequence of SEQ ID NO: 1; (ii) VH-CDR2 comprises the amino acidsequence of SEQ ID NO:2; (iii) VH-CDR3 comprises the amino acid sequenceof SEQ ID NO:3; (iv) VL-CDR1 comprises the amino acid sequence of SEQ IDNO:10; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 11;and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12;(b)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19; (ii)VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:21; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:28; (v) VL-CDR2 comprisesthe amino acid sequence of SEQ ID NO:29; and (vi) VL-CDR3 comprises theamino acid sequence of SEQ ID NO:30; (c)(i) VH-CDR1 comprises the aminoacid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acidsequence of SEQ ID NO:38; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:39; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO:46; (v) VL-CDR2 comprises the amino acid sequence of SEQ IDNO:47; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO:48; or (d)(i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:55; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:56;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO:64; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:65; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:66; and wherein theprotein binds ALK7.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs in which: (a)(i) VH-CDR1 comprises the aminoacid sequence of SEQ ID NO:88; (ii) VH-CDR2 comprises the amino acidsequence of SEQ ID NO:89; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:90; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ IDNO:96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO:97; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:103;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO:107; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:108; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:109; (c)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:114; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:115; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:116; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:121; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:122; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:123; (d)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO: 125; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO: 126; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:127; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:132; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:133; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:134; or (e)(i) VH-CDRcomprises the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:138; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:139; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:145; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:146; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:147; and wherein theprotein binds ALK7.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a VH and a VL pair selected from the group consisting of:(a)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:4, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:13;(b)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:22, or 132, and (ii) a VL having at least90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:31;(c)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:40, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:49; and(d)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:58, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:67; andwherein the protein binds ALK7.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a VH and a VL pair selected from the group consisting of:(a)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:91, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:98;(b)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:105, or 132, and (ii) a VL having atleast 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ IDNO:110; (c)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to SEQ ID NO: 117, and (ii) a VL having at least90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ IDNO:124; (d)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to SEQ ID NO:128, and (ii) a VL having at least90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ IDNO:135; and (e)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to SEQ ID NO:140, and (ii) a VL having at least90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:148; and wherein the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VLcontaining a VH sequence of SEQ ID NO:40 or 58, and a VL sequence of SEQID NO:49 or 67; and the protein binds ALK7. In a further embodiment, theALK7-binding protein comprises a VH sequence of SEQ ID NO:40 and a VLsequence of SEQ ID NO:49, and the protein binds ALK7. In a furtherembodiment, the ALK7-binding protein comprises a VH sequence of SEQ IDNO:58 and a VL sequence of SEQ ID NO:67, and the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VL paircomprising a VH sequence of SEQ ID NO:4 and a VL sequence of SEQ ID NO:13, and the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VL paircomprising a VH sequence of SEQ ID NO:22 and a VL sequence of SEQ IDNO:31, and the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VL paircomprising a VH sequence of SEQ ID NO:40 and a VL sequence of SEQ IDNO:49, and the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VL paircomprising a VH sequence of SEQ ID NO:58 and a VL sequence of SEQ IDNO:67, and the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VL paircomprising a VH sequence of SEQ ID NO:91 and a VL sequence of SEQ IDNO:98, and the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VL paircomprising a VH sequence of SEQ ID NO: 105 and a VL sequence of SEQ IDNO:110, and the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VL paircomprising a VH sequence of SEQ ID NO:117 and a VL sequence of SEQ IDNO:124, and the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VL paircomprising a VH sequence of SEQ ID NO: 128 and a VL sequence of SEQ IDNO: 135, and the protein binds ALK7.

In one embodiment, the ALK7-binding protein comprises a VH and a VL paircomprising a VH sequence of SEQ ID NO:140 and a VL sequence of SEQ IDNO:148, and the protein binds ALK7.

In some embodiments, the ALK7-binding protein comprises a VH and a VLpair selected from the group consisting of: (a)(i) a VH sequence havinga total of one, two, three, four, five, six, seven, eight, nine, ten,fewer than fifteen, or zero, amino acid substitutions, deletions, and/orinsertions from a reference VH sequence selected from the groupconsisting of SEQ ID NO:4, and (ii) a VL sequence having a total of one,two, three, four, five, six, seven, eight, nine, ten, fewer thanfifteen, or zero, amino acid substitutions, deletions, and/or insertionsfrom a reference VL sequence of SEQ ID NO: 13; (b)(i) a VH sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VH sequence of SEQ ID NO:22, and (ii)a VL sequence having a total of one, two, three, four, five, six, seven,eight, nine, ten, fewer than fifteen, or zero, amino acid substitutions,deletions, and/or insertions from a reference VL sequence of SEQ IDNO:31; (c)(i) a VH sequence having a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:40, and (ii) a VL sequence having a total of one,two, three, four, five, six, seven, eight, nine, ten, fewer thanfifteen, or zero, amino acid substitutions, deletions, and/or insertionsfrom a reference VL sequence of SEQ ID NO:49; and (d)(i) a VH sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VH sequence of SEQ ID NO:58, and (ii)a VL sequence having a total of one, two, three, four, five, six, seven,eight, nine, ten, fewer than fifteen, or zero, amino acid substitutions,deletions, and/or insertions from a reference VL sequence of SEQ IDNO:67; and wherein the protein binds ALK7.

In some embodiments, the ALK7-binding protein comprises a VH and a VLpair selected from the group consisting of: (a)(i) a VH sequence havinga total of one, two, three, four, five, six, seven, eight, nine, ten,fewer than fifteen, or zero, amino acid substitutions, deletions, and/orinsertions from a reference VH sequence selected from the groupconsisting of SEQ ID NO:91, and (ii) a VL sequence having a total ofone, two, three, four, five, six, seven, eight, nine, ten, fewer thanfifteen, or zero, amino acid substitutions, deletions, and/or insertionsfrom a reference VL sequence of SEQ ID NO:98; (b)(i) a VH sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VH sequence of SEQ ID NO: 105, and(ii) a VL sequence having a total of one, two, three, four, five, six,seven, eight, nine, ten, fewer than fifteen, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference VL sequenceof SEQ ID NO:110; (c)(i) a VH sequence having a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VH sequence of SEQ ID NO:117, and (ii) a VL sequence having atotal of one, two, three, four, five, six, seven, eight, nine, ten,fewer than fifteen, or zero, amino acid substitutions, deletions, and/orinsertions from a reference VL sequence of SEQ ID NO: 124; (d)(i) a VHsequence having a total of one, two, three, four, five, six, seven,eight, nine, ten, fewer than fifteen, or zero, amino acid substitutions,deletions, and/or insertions from a reference VH sequence of SEQ IDNO:128, and (ii) a VL sequence having a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VLsequence of SEQ ID NO:135; and (e)(i) a VH sequence having a total ofone, two, three, four, five, six, seven, eight, nine, ten, fewer thanfifteen, or zero, amino acid substitutions, deletions, and/or insertionsfrom a reference VH sequence of SEQ ID NO:140, and (ii) a VL sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VL sequence of SEQ ID NO: 148; andwherein the protein binds ALK7.

In some embodiments, the ALK7-binding protein is an antibody thatspecifically binds ALK7. In additional embodiments, the antibody is amonoclonal antibody, a recombinant antibody, a human antibody, ahumanized antibody, a chimeric antibody, a bi-specific antibody, or amulti-specific antibody. In some embodiments, the ALK7-binding proteinis an ALK7-binding antibody fragment. In some embodiments the antibodyis an antibody fragment selected from the group consisting of a Fab,Fab′, F(ab′)₂, Fv, diabody, DART, and a single chain antibody molecule(e.g., a BiTE).

In some embodiments, the ALK7-binding protein specifically binds to ALK7between amino acids 20-113 of SEQ ID NO:85. In some embodiments, theALK7-binding protein specifically binds to ALK7 between amino acids20-113 of SEQ ID NO:85 and inhibits one or more ALK ligands (e.g., GDF1,GDF3, GDF8, activin B, activin A/B, and/or Nodal) from binding to ALK7.In some embodiments, the ALK7-binding protein specifically binds to ALK7between amino acids 20-113 of SEQ ID NO: 85 and contacts one or moreamino acids selected from the group consisting of: (a) a Glu at position21 of SEQ ID NO:85; (b) a Leu at position 22 of SEQ ID NO:85; (c) a Serat position 23 of SEQ ID NO:85; (d) a Pro at position 24 of SEQ IDNO:85; (e) a Gly at position 25 of SEQ ID NO:85; (f) a Leu at position26 of SEQ ID NO:85; (g) a Lys at position 27 of SEQ ID NO:85; (h) a Cysat position 28 of SEQ ID NO:85; (i) a Val at position 29 of SEQ IDNO:85; (j) a Cys at position 30 of SEQ ID NO:85; (k) a Leu at position31 of SEQ ID NO:85; (l) a Leu at position 32 of SEQ ID NO:85; (m) a Cysat position 33 of SEQ ID NO:85; (n) a Asp at position 34 of SEQ IDNO:85; (o) a Ser at position 35 of SEQ ID NO:85; (p) a Ser at position36 of SEQ ID NO:85; (q) a Asn at position 37 of SEQ ID NO:85; (r) a Pheat position 38 of SEQ ID NO:85; (s) a Thr at position 39 of SEQ IDNO:85; (t) a Cys at position 40 of SEQ ID NO:85; (u) a Gln at position41 of SEQ ID NO:85; (v) a Thr at position 42 of SEQ ID NO:85; (w) a Gluat position 43 of SEQ ID NO:85; (x) a Gly at position 44 of SEQ IDNO:85; (y) a Ala at position 45 of SEQ ID NO:85; (z) a Cys at position46 of SEQ ID NO:85; (aa) a Trp at position 47 of SEQ ID NO:85; (ab) aAla at position 48 of SEQ ID NO:85; (ac) a Ser at position 49 of SEQ IDNO:85; (ad) a Val at position 50 of SEQ ID NO:85; (ae) a Met at position51 of SEQ ID NO:85; (af) a Leu at position 52 of SEQ ID NO:85; (ag) aThr at position 53 of SEQ ID NO:85; (ah) a Asn at position 54 of SEQ IDNO:85; (ai) a Gly at position 55 of SEQ ID NO:85; (aj) a Lys at position56 of SEQ ID NO:85; (ak) a Glu at position 57 of SEQ ID NO:85; (al) aGln at position 58 of SEQ ID NO:85; (am) a Val at position 59 of SEQ IDNO:85; (an) a lie at position 60 of SEQ ID NO:85; (ao) a Lys at position61 of SEQ ID NO:85; (ap) a Ser at position 62 of SEQ ID NO:85; (aq) aCys at position 63 of SEQ ID NO:85; (ar) a Val at position 64 of SEQ IDNO:85; (as) a Ser at position 65 of SEQ ID NO:85; (at) a Leu at position66 of SEQ ID NO:85; (au) a Pro at position 67 of SEQ ID NO:85; (av) aGlu at position 68 of SEQ ID NO:85; (aw) a Leu at position 69 of SEQ IDNO:85; (ax) a Asn at position 70 of SEQ ID NO:85; (ay) a Ala at position71 of SEQ ID NO:85; (az) a Gln at position 72 of SEQ ID NO:85; (ba) aVal at position 73 of SEQ ID NO:85; (bb) a Phe at position 74 of SEQ IDNO:85; (be) a Cys at position 75 of SEQ ID NO:85; (bd) a His at position76 of SEQ ID NO:85; (be) a Ser at position 77 of SEQ ID NO:85; (bf) aSer at position 78 of SEQ ID NO:85; (bg) a Asn at position 79 of SEQ IDNO:85; (bh) a Asn at position 80 of SEQ ID NO:85; (bi) a Val at position81 of SEQ ID NO:85; (bj) a Thr at position 82 of SEQ ID NO:85; (bk) aLys at position 83 of SEQ ID NO:85; (bl) a Thr at position 84 of SEQ IDNO:85; (bm) a Glu at position 85 of SEQ ID NO:85; (bn) a Cys at position86 of SEQ ID NO:85; (bo) a Cys at position 87 of SEQ ID NO:85; (bp) aPhe at position 88 of SEQ ID NO:85; (bq) a Thr at position 89 of SEQ IDNO:85; (br) a Asp at position 90 of SEQ ID NO:85; (bs) a Phe at position91 of SEQ ID NO:85; (bt) a Cys at position 92 of SEQ ID NO:85; (bu) aAsn at position 93 of SEQ ID NO:85; (bv) a Asn at position 94 of SEQ IDNO:85; (bw) a Ile at position 95 of SEQ ID NO:85; (bx) a Thr at position96 of SEQ ID NO:85; (by) a Leu at position 97 of SEQ ID NO:85; (bz) aHis at position 98 of SEQ ID NO:85; (ca) a Leu at position 99 of SEQ IDNO:85; (cb) a Pro at position 100 of SEQ ID NO:85; (cc) a Thr atposition 101 of SEQ ID NO:85; (cd) a Ala at position 102 of SEQ IDNO:85; (ce) a Ser at position 103 of SEQ ID NO:85; (cf) a Pro atposition 104 of SEQ ID NO:85; (cg) a Asn at position 105 of SEQ IDNO:85; (ch) a Ala at position 106 of SEQ ID NO:85; (ci) a Pro atposition 107 of SEQ ID NO:85; (cj) a Lys at position 108 of SEQ IDNO:85; (ck) a Leu at position 109 of SEQ ID NO:85; (cl) a Gly atposition 110 of SEQ ID NO:85; (cm) a Pro at position 111 of SEQ IDNO:85: (cn) a Met at position 112 of SEQ ID NO:85; and (co) a Glu atposition 113 of SEQ ID NO:85. In some embodiments, the ALK7-bindingprotein specifically binds to ALK7 between amino acids 20-113 of SEQ IDNO: 85 and contacts one or more amino acids selected from the groupconsisting of: (a) a Glu at position 21 of SEQ ID NO:85; (b) a Leu atposition 22 of SEQ ID NO:85; (c) a Ser at position 23 of SEQ ID NO:85;(d) a Pro at position 24 of SEQ ID NO:85; (e) a Gly at position 25 ofSEQ ID NO:85; (f) a Leu at position 26 of SEQ ID NO:85; (g) a Lys atposition 27 of SEQ ID NO:85; (h) a Cys at position 28 of SEQ ID NO:85;(i) a Val at position 29 of SEQ ID NO:85; (j) a Cys at position 30 ofSEQ ID NO:85; (k) a Leu at position 31 of SEQ ID NO:85; (l) a Leu atposition 32 of SEQ ID NO:85; (m) a Cys at position 33 of SEQ ID NO:85;(n) a Asp at position 34 of SEQ ID NO:85; (o) a Ser at position 35 ofSEQ ID NO:85; (p) a Ser at position 36 of SEQ ID NO:85; (q) a Asn atposition 37 of SEQ ID NO:85; (r) a Phe at position 38 of SEQ ID NO:85;(s) a Thr at position 39 of SEQ ID NO:85; (t) a Cys at position 40 ofSEQ ID NO:85; (u) a Gln at position 41 of SEQ ID NO:85; (v) a Thr atposition 42 of SEQ ID NO:85; (w) a Glu at position 43 of SEQ ID NO:85;(x) a Gly at position 44 of SEQ ID NO:85; (y) a Ala at position 45 ofSEQ ID NO:85; (z) a Cys at position 46 of SEQ ID NO:85; (aa) a Trp atposition 47 of SEQ ID NO:85; (ab) a Ala at position 48 of SEQ ID NO:85;(ac) a Ser at position 49 of SEQ ID NO:85; (ad) a Val at position 50 ofSEQ ID NO:85; (ae) a Met at position 51 of SEQ ID NO:85; (af) a Leu atposition 52 of SEQ ID NO:85; (ag) a Thr at position 53 of SEQ ID NO:85;(ah) a Asn at position 54 of SEQ ID NO:85; (ai) a Gly at position 55 ofSEQ ID NO:85; (aj) a Lys at position 56 of SEQ ID NO:85; (ak) a Glu atposition 57 of SEQ ID NO:85; (al) a Gln at position 58 of SEQ ID NO:85;(am) a Val at position 59 of SEQ ID NO:85; (an) a Ile at position 60 ofSEQ ID NO:85; (ao) a Lys at position 61 of SEQ ID NO:85; (ap) a Ser atposition 62 of SEQ ID NO:85; (aq) a Cys at position 63 of SEQ ID NO:85;(ar) a Val at position 64 of SEQ ID NO:85; (as) a Ser at position 65 ofSEQ ID NO:85; (at) a Leu at position 66 of SEQ ID NO:85; (au) a Pro atposition 67 of SEQ ID NO:85; (av) a Glu at position 68 of SEQ ID NO:85;(aw) a Leu at position 69 of SEQ ID NO:85; (ax) a Asn at position 70 ofSEQ ID NO:85; (ay) a Ala at position 71 of SEQ ID NO:85; (az) a Gln atposition 72 of SEQ ID NO:85; (ba) a Val at position 73 of SEQ ID NO:85;(bb) a Phe at position 74 of SEQ ID NO:85; (bc) a Cys at position 75 ofSEQ ID NO:85; (bd) a His at position 76 of SEQ ID NO:85; (be) a Ser atposition 77 of SEQ ID NO:85; (bf) a Ser at position 78 of SEQ ID NO:85;(bg) a Asn at position 79 of SEQ ID NO:85; (bh) a Asn at position 80 ofSEQ TD NO:85; (bi) a Val at position 81 of SEQ ID NO:85; (bj) a Thr atposition 82 of SEQ ID NO:85; (bk) a Lys at position 83 of SEQ ID NO:85;(bl) a Thr at position 84 of SEQ ID NO:85; (bm) a Glu at position 85 ofSEQ ID NO:85; (bn) a Cys at position 86 of SEQ ID NO:85; (bo) a Cys atposition 87 of SEQ ID NO:85; (bp) a Phe at position 88 of SEQ ID NO:85;(bq) a Thr at position 89 of SEQ ID NO:85; (br) a Asp at position 90 ofSEQ ID NO:85; (bs) a Phe at position 91 of SEQ ID NO:85; (bt) a Cys atposition 92 of SEQ ID NO:85; (bu) a Asn at position 93 of SEQ ID NO:85;(bv) a Asn at position 94 of SEQ ID NO:85; (bw) a Ile at position 95 ofSEQ ID NO:85; (bx) a Thr at position 96 of SEQ ID NO:85; (by) a Leu atposition 97 of SEQ ID NO:85; (bz) a His at position 98 of SEQ ID NO:85;(ca) a Leu at position 99 of SEQ ID NO:85; (cb) a Pro at position 100 ofSEQ ID NO:85; (cc) a Thr at position 101 of SEQ ID NO:85; (cd) a Ala atposition 102 of SEQ ID NO:85; (ce) a Ser at position 103 of SEQ IDNO:85; (cf) a Pro at position 104 of SEQ ID NO:85; (cg) a Asn atposition 105 of SEQ ID NO:85; (ch) a Ala at position 106 of SEQ IDNO:85; (ci) a Pro at position 107 of SEQ ID NO:85; (cj) a Lys atposition 108 of SEQ ID NO:85; (ck) a Leu at position 109 of SEQ IDNO:85; (cl) a Gly at position 110 of SEQ ID NO:85; (cm) a Pro atposition 111 of SEQ ID NO:85; (cn) a Met at position 112 of SEQ IDNO:85; and (co) a Glu at position 113 of SEQ ID NO:85; and inhibits oneor more ALK7 ligands (e.g., GDF1, GDF3, GDF8, activin B, activin A/B,and/or Nodal) from binding to ALK7. In some embodiments, theALK7-binding protein specifically binds to ALK7 between amino acids20-113 of SEQ ID NO:85 and increases lipolysis (e.g., lipolysis of whiteadipocytes and/or brown adipocytes). In some embodiments, theALK7-binding protein specifically binds to ALK7 between amino acids20-113 of SEQ ID NO: 85 and contacts one or more amino acids selectedfrom the group consisting of: (a) a Glu at position 21 of SEQ ID NO:85;(b) a Leu at position 22 of SEQ ID NO:85; (c) a Ser at position 23 ofSEQ ID NO:85; (d) a Pro at position 24 of SEQ ID NO:85; (e) a Gly atposition 25 of SEQ ID NO:85; (f) a Leu at position 26 of SEQ ID NO:85;(g) a Lys at position 27 of SEQ ID NO:85; (h) a Cys at position 28 ofSEQ ID NO:85; (i) a Val at position 29 of SEQ ID NO:85; (j) a Cys atposition 30 of SEQ ID NO:85; (k) a Leu at position 31 of SEQ ID NO:85;(l) a Leu at position 32 of SEQ ID NO:85; (m) a Cys at position 33 ofSEQ ID NO:85; (n) a Asp at position 34 of SEQ ID NO:85; (o) a Ser atposition 35 of SEQ ID NO:85; (p) a Ser at position 36 of SEQ ID NO:85;(q) a Asn at position 37 of SEQ ID NO:85; (r) a Phe at position 38 ofSEQ ID NO:85; (s) a Thr at position 39 of SEQ ID NO:85; (t) a Cys atposition 40 of SEQ ID NO:85; (u) a Gln at position 41 of SEQ ID NO:85;(v) a Thr at position 42 of SEQ ID NO:85; (w) a Glu at position 43 ofSEQ ID NO:85; (x) a Gly at position 44 of SEQ ID NO:85; (y) a Ala atposition 45 of SEQ ID NO:85; (z) a Cys at position 46 of SEQ ID NO:85;(aa) a Trp at position 47 of SEQ ID NO:85: (ab) a Ala at position 48 ofSEQ ID NO:85; (ac) a Ser at position 49 of SEQ ID NO:85; (ad) a Val atposition 50 of SEQ ID NO:85; (ae) a Met at position 51 of SEQ ID NO:85;(af) a Leu at position 52 of SEQ ID NO:85; (ag) a Thr at position 53 ofSEQ ID NO:85; (ah) a Asn at position 54 of SEQ ID NO:85; (ai) a Gly atposition 55 of SEQ ID NO:85; (aj) a Lys at position 56 of SEQ ID NO:85;(ak) a Glu at position 57 of SEQ ID NO:85; (al) a Gln at position 58 ofSEQ ID NO:85; (am) a Val at position 59 of SEQ ID NO:85; (an) a lie atposition 60 of SEQ ID NO:85; (ao) a Lys at position 61 of SEQ ID NO:85;(ap) a Ser at position 62 of SEQ ID NO:85; (aq) a Cys at position 63 ofSEQ ID NO:85; (ar) a Val at position 64 of SEQ ID NO:85; (as) a Ser atposition 65 of SEQ ID NO:85; (at) a Leu at position 66 of SEQ ID NO:85;(au) a Pro at position 67 of SEQ ID NO:85; (av) a Glu at position 68 ofSEQ ID NO:85; (aw) a Leu at position 69 of SEQ ID NO:85; (ax) a Asn atposition 70 of SEQ ID NO:85; (ay) a Ala at position 71 of SEQ ID NO:85;(az) a Gln at position 72 of SEQ ID NO:85; (ba) a Val at position 73 ofSEQ ID NO:85; (bb) a Phe at position 74 of SEQ ID NO:85; (be) a Cys atposition 75 of SEQ ID NO:85; (bd) a His at position 76 of SEQ ID NO:85;(be) a Ser at position 77 of SEQ ID NO:85; (bf) a Ser at position 78 ofSEQ ID NO:85; (bg) a Asn at position 79 of SEQ ID NO:85; (bh) a Asn atposition 80 of SEQ ID NO:85; (bi) a Val at position 81 of SEQ ID NO:85;(bj) a Thr at position 82 of SEQ ID NO:85; (bk) a Lys at position 83 ofSEQ ID NO:85; (bl) a Thr at position 84 of SEQ ID NO:85; (bm) a Glu atposition 85 of SEQ ID NO:85; (bn) a Cys at position 86 of SEQ ID NO:85;(bo) a Cys at position 87 of SEQ ID NO:85; (bp) a Phe at position 88 ofSEQ ID NO:85; (bq) a Thr at position 89 of SEQ ID NO:85; (br) a Asp atposition 90 of SEQ ID NO:85; (bs) a Phe at position 91 of SEQ ID NO:85;(bt) a Cys at position 92 of SEQ ID NO:85; (bu) a Asn at position 93 ofSEQ ID NO:85; (bv) a Asn at position 94 of SEQ ID NO:85; (bw) a Ile atposition 95 of SEQ ID NO:85; (bx) a Thr at position 96 of SEQ ID NO:85;(by) a Leu at position 97 of SEQ ID NO:85; (bz) a His at position 98 ofSEQ ID NO:85; (ca) a Leu at position 99 of SEQ ID NO:85; (cb) a Pro atposition 100 of SEQ ID NO:85; (cc) a Thr at position 101 of SEQ IDNO:85; (cd) a Ala at position 102 of SEQ ID NO:85; (ce) a Ser atposition 103 of SEQ ID NO:85; (cf) a Pro at position 104 of SEQ IDNO:85; (cg) a Asn at position 105 of SEQ ID NO:85; (ch) a Ala atposition 106 of SEQ ID NO:85; (ci) a Pro at position 107 of SEQ IDNO:85; (cj) a Lys at position 108 of SEQ ID NO:85; (ck) a Leu atposition 109 of SEQ ID NO:85; (cl) a Gly at position 110 of SEQ IDNO:85; (cm) a Pro at position 111 of SEQ ID NO:85; (cn) a Met atposition 112 of SEQ ID NO:85; and (co) a Glu at position 113 of SEQ IDNO:85; and increases lipolysis (e.g., lipolysis of white adipocytesand/or brown adipocytes).

In some embodiments, the ALK7-binding protein specifically binds to ALK7between amino acids 28-92 of SEQ ID NO:85. In some embodiments, theALK7-binding protein specifically binds to ALK7 between amino acids28-92 of SEQ ID NO:85 and inhibits one or more ALK7 ligands (e.g., GDF1,GDF3, GDF8, activin B, activin A/B, and/or Nodal) from binding to ALK7.In some embodiments, the ALK7-binding protein specifically binds to ALK7between amino acids 28-92 of SEQ ID NO:85 and contacts one or more aminoacids selected from the group consisting of: (a) a Cys at position 28 ofSEQ ID NO:85; (b) a Val at position 29 of SEQ ID NO:85; (c) a Cys atposition 30 of SEQ ID NO:85; (d) a Leu at position 31 of SEQ ID NO:85;(e) a Leu at position 32 of SEQ ID NO:85; (f) a Cys at position 33 ofSEQ ID NO:85; (g) a Asp at position 34 of SEQ ID NO:85; (h) a Ser atposition 35 of SEQ ID NO:85; (i) a Ser at position 36 of SEQ ID NO:85;(j) a Asn at position 37 of SEQ ID NO:85; (k) a Phe at position 38 ofSEQ ID NO:85; (l) a Thr at position 39 of SEQ ID NO:85; (m) a Cys atposition 40 of SEQ ID NO:85; (n) a Gln at position 41 of SEQ ID NO:85;(o) a Thr at position 42 of SEQ ID NO:85; (p) a Glu at position 43 ofSEQ ID NO:85; (q) a Gly at position 44 of SEQ ID NO:85; (r) a Ala atposition 45 of SEQ ID NO:85; (s) a Cys at position 46 of SEQ ID NO:85;(t) a Trp at position 47 of SEQ ID NO:85; (u) a Ala at position 48 ofSEQ ID NO:85; (v) a Ser at position 49 of SEQ ID NO:85; (w) a Val atposition 50 of SEQ ID NO:85; (x) a Met at position 51 of SEQ ID NO:85;(y) a Leu at position 52 of SEQ ID NO:85; (z) a Thr at position 53 ofSEQ ID NO:85; (aa) a Asn at position 54 of SEQ ID NO:85; (ab) a Gly atposition 55 of SEQ ID NO:85; (ac) a Lys at position 56 of SEQ ID NO:85;(ad) a Glu at position 57 of SEQ ID NO:85; (ae) a Gln at position 58 ofSEQ ID NO:85; (af) a Val at position 59 of SEQ ID NO:85; (ag) a Ile atposition 60 of SEQ ID NO:85; (ah) a Lys at position 61 of SEQ ID NO:85;(ai) a Ser at position 62 of SEQ ID NO:85; (aj) a Cys at position 63 ofSEQ ID NO:85; (ak) a Val at position 64 of SEQ ID NO:85; (al) a Ser atposition 65 of SEQ ID NO:85; (am) a Leu at position 66 of SEQ ID NO:85;(an) a Pro at position 67 of SEQ ID NO:85; (ao) a Glu at position 68 ofSEQ ID NO:85; (ap) a Leu at position 69 of SEQ ID NO:85; (aq) a Asn atposition 70 of SEQ ID NO:85; (ar) a Ala at position 71 of SEQ ID NO:85;(as) a Gln at position 72 of SEQ ID NO:85; (at) a Val at position 73 ofSEQ ID NO:85; (au) a Phe at position 74 of SEQ ID NO:85; (av) a Cys atposition 75 of SEQ ID NO:85; (aw) a His at position 76 of SEQ ID NO:85;(ax) a Ser at position 77 of SEQ ID NO:85; (ay) a Ser at position 78 ofSEQ ID NO:85; (az) a Asn at position 79 of SEQ ID NO:85; (ba) a Asn atposition 80 of SEQ ID NO:85; (bb) a Val at position 81 of SEQ ID NO:85;(bc) a Thr at position 82 of SEQ ID NO:85; (bd) a Lys at position 83 ofSEQ ID NO:85; (be) a Thr at position 84 of SEQ ID NO:85; (bf) a Glu atposition 85 of SEQ ID NO:85; (bg) a Cys at position 86 of SEQ ID NO:85;(bh) a Cys at position 87 of SEQ ID NO:85; (bi) a Phe at position 88 ofSEQ ID NO:85; (bj) a Thr at position 89 of SEQ ID NO:85; (bk) a Asp atposition 90 of SEQ ID NO:85: (bl) a Phe at position 91 of SEQ ID NO:85;and (bm) a Cys at position 92 of SEQ ID NO:85. In some embodiments, theALK7-binding protein specifically binds to ALK7 between amino acids28-92 of SEQ ID NO: 85 and contacts one or more amino acids selectedfrom the group consisting of: (a) a Cys at position 28 of SEQ ID NO:85;(b) a Val at position 29 of SEQ ID NO:85; (c) a Cys at position 30 ofSEQ ID NO:85; (d) a Leu at position 31 of SEQ ID NO:85; (e) a Leu atposition 32 of SEQ ID NO:85; (f) a Cys at position 33 of SEQ ID NO:85;(g) a Asp at position 34 of SEQ ID NO:85; (h) a Ser at position 35 ofSEQ ID NO:85; (i) a Ser at position 36 of SEQ ID NO:85; (j) a Asn atposition 37 of SEQ ID NO:85; (k) a Phe at position 38 of SEQ ID NO:85;(l) a Thr at position 39 of SEQ ID NO:85; (m) a Cys at position 40 ofSEQ II) NO:85; (n) a Gln at position 41 of SEQ ID NO:85; (o) a Thr atposition 42 of SEQ ID NO:85; (p) a Glu at position 43 of SEQ ID NO:85;(q) a Gly at position 44 of SEQ ID NO:85; (r) a Ala at position 45 ofSEQ ID NO:85; (s) a Cys at position 46 of SEQ ID NO:85; (t) a Trp atposition 47 of SEQ ID NO:85; (u) a Ala at position 48 of SEQ ID NO:85;(v) a Ser at position 49 of SEQ ID NO:85; (w) a Val at position 50 ofSEQ ID NO:85; (x) a Met at position 51 of SEQ ID NO:85; (y) a Leu atposition 52 of SEQ ID NO:85; (z) a Thr at position 53 of SEQ ID NO:85;(aa) a Asn at position 54 of SEQ ID NO:85; (ab) a Gly at position 55 ofSEQ ID NO:85; (ac) a Lys at position 56 of SEQ ID NO:85; (ad) a Glu atposition 57 of SEQ ID NO:85; (ae) a Gln at position 58 of SEQ ID NO:85;(af) a Val at position 59 of SEQ ID NO:85; (ag) a lie at position 60 ofSEQ ID NO:85; (ah) a Lys at position 61 of SEQ ID NO:85; (ai) a Ser atposition 62 of SEQ ID NO:85; (aj) a Cys at position 63 of SEQ ID NO:85;(ak) a Val at position 64 of SEQ ID NO:85; (al) a Ser at position 65 ofSEQ ID NO:85; (am) a Leu at position 66 of SEQ ID NO:85; (an) a Pro atposition 67 of SEQ ID NO:85; (ao) a Glu at position 68 of SEQ ID NO:85;(ap) a Leu at position 69 of SEQ ID NO:85; (aq) a Asn at position 70 ofSEQ ID NO:85; (ar) a Ala at position 71 of SEQ ID NO:85; (as) a Gln atposition 72 of SEQ ID NO:85; (at) a Val at position 73 of SEQ ID NO:85;(au) a Phe at position 74 of SEQ ID NO:85; (av) a Cys at position 75 ofSEQ ID NO:85; (aw) a His at position 76 of SEQ ID NO:85; (ax) a Ser atposition 77 of SEQ ID NO:85; (ay) a Ser at position 78 of SEQ ID NO:85;(az) a Asn at position 79 of SEQ ID NO:85; (ba) a Asn at position 80 ofSEQ ID NO:85; (bb) a Val at position 81 of SEQ ID NO:85; (bc) a Thr atposition 82 of SEQ ID NO:85; (bd) a Lys at position 83 of SEQ ID NO:85;(be) a Thr at position 84 of SEQ ID NO:85; (bf) a Glu at position 85 ofSEQ ID NO:85; (bg) a Cys at position 86 of SEQ ID NO:85; (bh) a Cys atposition 87 of SEQ ID NO:85; (bi) a Phe at position 88 of SEQ ID NO:85;(bj) a Thr at position 89 of SEQ ID NO:85; (bk) a Asp at position 90 ofSEQ ID NO:85; (bl) a Phe at position 91 of SEQ ID NO:85; and (bm) a Cysat position 92 of SEQ ID NO:85; and inhibits one or more ALK7 ligands(e.g., GDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal) frombinding to ALK7. In some embodiments, the ALK7-binding proteinspecifically binds to ALK7 between amino acids 28-92 of SEQ ID NO:85 andincreases lipolysis (e.g., lipolysis of white adipocytes and/or brownadipocytes). In some embodiments, the ALK7-binding protein specificallybinds to ALK7 between amino acids 28-92 of SEQ ID NO:85 and contacts oneor more amino acids selected from the group consisting of: (a) a Cys atposition 28 of SEQ ID NO:85; (b) a Val at position 29 of SEQ ID NO:85;(c) a Cys at position 30 of SEQ ID NO:85; (d) a Leu at position 31 ofSEQ ID NO:85; (e) a Leu at position 32 of SEQ ID NO:85; (f) a Cys atposition 33 of SEQ ID NO:85; (g) a Asp at position 34 of SEQ ID NO:85;(h) a Ser at position 35 of SEQ ID NO:85; (i) a Ser at position 36 ofSEQ ID NO:85; (j) a Asn at position 37 of SEQ ID NO:85; (k) a Phe atposition 38 of SEQ ID NO:85; (l) a Thr at position 39 of SEQ ID NO:85;(m) a Cys at position 40 of SEQ ID NO:85; (n) a Gln at position 41 ofSEQ ID NO:85; (o) a Thr at position 42 of SEQ ID NO:85; (p) a Glu atposition 43 of SEQ ID NO:85; (q) a Gly at position 44 of SEQ ID NO:85;(r) a Ala at position 45 of SEQ ID NO:85; (s) a Cys at position 46 ofSEQ ID NO:85; (t) a Trp at position 47 of SEQ ID NO:85; (u) a Ala atposition 48 of SEQ ID NO:85; (v) a Ser at position 49 of SEQ ID NO:85;(w) a Val at position 50 of SEQ ID NO:85; (x) a Met at position 51 ofSEQ ID NO:85; (y) a Leu at position 52 of SEQ ID NO:85; (z) a Thr atposition 53 of SEQ ID NO:85; (aa) a Asn at position 54 of SEQ ID NO:85;(ab) a Gly at position 55 of SEQ ID NO:85; (ac) a Lys at position 56 ofSEQ ID NO:85; (ad) a Glu at position 57 of SEQ ID NO:85; (ae) a Gln atposition 58 of SEQ ID NO:85; (af) a Val at position 59 of SEQ ID NO:85;(ag) a lie at position 60 of SEQ ID NO:85; (ah) a Lys at position 61 ofSEQ ID NO:85; (ai) a Ser at position 62 of SEQ ID NO:85; (aj) a Cys atposition 63 of SEQ ID NO:85; (ak) a Val at position 64 of SEQ ID NO:85;(al) a Ser at position 65 of SEQ ID NO:85; (am) a Leu at position 66 ofSEQ ID NO:85; (an) a Pro at position 67 of SEQ ID NO:85; (ao) a Glu atposition 68 of SEQ ID NO:85; (ap) a Leu at position 69 of SEQ ID NO:85;(aq) a Asn at position 70 of SEQ ID NO:85; (ar) a Ala at position 71 ofSEQ ID NO:85; (as) a Gln at position 72 of SEQ ID NO:85; (at) a Val atposition 73 of SEQ ID NO:85; (au) a Phe at position 74 of SEQ ID NO:85;(av) a Cys at position 75 of SEQ ID NO:85; (aw) a His at position 76 ofSEQ ID NO:85; (ax) a Ser at position 77 of SEQ ID NO:85; (ay) a Ser atposition 78 of SEQ ID NO:85; (az) a Asn at position 79 of SEQ ID NO:85;(ba) a Asn at position 80 of SEQ ID NO:85; (bb) a Val at position 81 ofSEQ ID NO:85; (bc) a Thr at position 82 of SEQ ID NO:85; (bd) a Lys atposition 83 of SEQ ID NO:85; (be) a Thr at position 84 of SEQ ID NO:85;(bf) a Glu at position 85 of SEQ ID NO:85; (bg) a Cys at position 86 ofSEQ ID NO:85; (bh) a Cys at position 87 of SEQ ID NO:85; (bi) a Phe atposition 88 of SEQ ID NO:85; (bj) a Thr at position 89 of SEQ ID NO:85;(bk) a Asp at position 90 of SEQ ID NO:85; (bl) a Phe at position 91 ofSEQ ID NO:85; and (bm) a Cys at position 92 of SEQ ID NO:85; andincreases lipolysis (e.g., lipolysis of white adipocytes and/or brownadipocytes).

Nucleic acids and sets of nucleic acids encoding ALK7-binding proteinsare also provided. Vectors and sets of vectors containing the nucleicacids and sets of nucleic acids, and host cells transformed with thenucleic acids and vectors are further provided. In some embodiments, thehost cell is a hybridoma or mammalian host cell such as, a NS0 murinemyeloma cell, a PER.C6® human cell, or a Chinese hamster ovary (CHO)cell. Host cells including mammalian host cells and hybridomas thatproduce ALK7-binding proteins are also provided.

Methods for making an ALK7-binding protein are also provided. In someembodiments, the method comprises culturing a host cell capable ofexpressing the ALK7-binding protein under suitable conditions forexpressing the protein and optionally isolating the expressedALK7-binding protein. ALK7-binding proteins prepared and/or isolatedusing methods disclosed herein or otherwise known in the art are alsoprovided.

Pharmaceutical compositions comprising an ALK7-binding protein and apharmaceutically acceptable carrier are further provided. In someembodiments, the disclosure provides methods for treating and/orameliorating a condition in a subject associated with elevated ALK7expression or ALK7-mediated signaling, or that can be treated and/orameliorated by decreased ALK7 signaling. In some embodiments, themethods decrease ALK7-mediated signaling in the subject.

Conditions that may be treated and/or ameliorated in a subject using theprovided methods include, but are not limited to: obesity (e.g.,abdominal obesity); overweight; insulin resistance; metabolic syndromeand other metabolic diseases or conditions; a lipid disorder such as,low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia ordyslipidemia; lipoprotein aberrations; decreased triglycerides;inflammation (e.g., liver inflammation and/or inflammation of adiposetissue), fatty liver disease; non-alcoholic fatty liver disease;hyperglycemia; impaired glucose tolerance (IGT); hyperinsulinemia; highcholesterol (e.g., high LDL levels and hypercholesterolemia);cardiovascular disease such as, heart disease including coronary heartdisease, congestive heart failure, stroke, peripheral vascular disease,disordered fibrinolysis, atherosclerosis; arteriosclerosis, andhypertension; Syndrome X; vascular restenosis; neuropathy; retinopathy;neurodegenerative disease; endothelial dysfunction, respiratorydysfunction, renal disease (e.g., nephropathy); pancreatitis; polycysticovarian syndrome; elevated uric acid levels; haemochromatosis (ironoverload); acanthosis nigricans (dark patches on the skin); and cancer(e.g., myeloma (multiple myeloma, plasmacytoma, localized myeloma, orextramedullary myeloma), or an ovarian, breast, colon, endometrial,liver, kidney, pancreatic, gastric, uterine and/or colon cancer); andother disorders/conditions associated with one or more of the abovediseases or conditions, or with overweight (e.g., BMI≥25 kg/m²), or toomuch body fat.

In some embodiments, the disclosed methods include administering apharmaceutical composition comprising an effective amount of anALK7-binding protein (e.g., an antagonist ALK7 binding protein such asan antagonist anti-ALK7 antibody) to a subject in need thereof. In someembodiments, the ALK7-binding protein is administered alone. In otherembodiments, the ALK7-binding protein is administered as a combinationtherapy. In further embodiments, the ALK7-binding protein isadministered as a combination therapy to the standard of caretreatment/therapy.

Methods of blocking or reducing ALK7 activity (e.g., ligand bindingand/or signaling) are also provided. In some embodiments the methodcomprises contacting an ALK7-binding protein and a cell that expressesALK7, (e.g., a differentiated white or brown adipocyte). In someinstances the method comprises contacting an ALK7-binding protein and acell that expresses ALK7, in the presence of GDF1, GDF3, GDF8, activinB, activin A/B, and/or Nodal. In some embodiments, the method isperformed in vivo. In other embodiments, the method is performed invitro. In some embodiments the blocked or reduced ALK7 activity is thephosphorylation of ALK7. In additional embodiments the blocked orreduced ALK7 activity is the phosphorylation of Smads (e.g., Smad2and/or Smad3). In some embodiments, the disclosure provides a method ofblocking or reducing ALK7 activity in a subject that comprisesadministering an effective amount of an ALK7-binding protein to asubject in need thereof.

Also provided is a method of blocking or reducing ALK7 activity in apathological condition associated with ALK7 expression and/or ALK7signaling, or in a pathological condition that can be treated and/orameliorated by reducing or inhibiting the activity of an ALK7-ligand. Insome instances, the method comprises administering an ALK7-bindingprotein to a subject having increased expression of ALK7 or anALK7-ligand. In some embodiments, the pathological condition is obesity,diabetes, metabolic disease, dyslipidemia; cardiovascular disease, type2 diabetes, inflammation, or a pulmonary, fatty liver disease,neurologic, and hepatic, or renal disease.

In one embodiment, the disclosure provides a method of treating orameliorating overweight or a condition associated with being overweight,comprising administering to an overweight subject an effective amount ofan ALK7-binding protein (e.g., an antagonist ALK7 binding protein suchas an antagonist anti-ALK7 antibody). In one embodiment, the he treatedor ameliorated condition is obesity. In another embodiment, the treatedor ameliorated condition is a member selected from the group consistingof dyslipidemia, hyperlipidemia, hypercholesterolemia, low HDL serumlevel, high LDL serum level (e.g., LDL-C≥100 mg/dL, ≥130 mg/dL, ≥160mg/dL), and hypertriglyceridemia (e.g., TG≥150 mg/dL, ≥160 mg/dL, ≥170mg/dL). In another embodiment, the treated or ameliorated condition ishypertension. In another embodiment, the treated or amelioratedcondition is diabetes. In one embodiment, the administered ALK7-bindingprotein is an ALK7 antagonist. In one embodiment, the administeredantagonist ALK7-binding protein is an anti-ALK7 antibody or anALK7-binding antibody fragment. In another embodiment the administeredantagonist ALK7-binding protein is an anti-ALK7 antibody or anALK7-binding antibody fragment disclosed herein. In one embodiment, theadministered ALK7-binding protein comprises a VH and VL pair disclosedin Table 1A. In another embodiment, the administered ALK7-bindingprotein cross-blocks or competes for binding to ALK7 with an antibodycomprising a VH and a VL sequence pair disclosed in Table 1A. In oneembodiment, the administered ALK7-binding protein comprises a VH and VLpair disclosed in Table 1B or Table 3. In another embodiment, theadministered ALK7-binding protein cross-blocks or competes for bindingto ALK7 with an antibody comprising a VH and a VL sequence pairdisclosed in Table 1B or Table 3. In one embodiment, the administeredALK7-binding protein comprises a VH and VL pair disclosed in Table 1A,Table 1B, or Table 3. In another embodiment, the administeredALK7-binding protein cross-blocks or competes for binding to ALK7 withan antibody comprising a VH and a VL sequence pair disclosed in Table1A, Table 1B, or Table 3.

In one embodiment, the disclosure provides a method of treating orameliorating obesity or a condition associated with obesity, comprisingadministering to an obese subject an effective amount of an ALK7-bindingprotein (e.g., an antagonist ALK7 binding protein such as an antagonistanti-ALK7 antibody). In one embodiment the treated or amelioratedcondition is hypertension, dyslipidemia (for example, high totalcholesterol or high levels of triglycerides), type 2 diabetes, coronaryheart disease, stroke, gallbladder disease, osteoarthritis, sleepdisorders, respiratory problems, cancer (e.g., myeloma (multiplemyeloma, plasmacytoma, localized myeloma, or extramedullary myeloma), oran ovarian, breast, colon, endometrial, liver, kidney, pancreatic,gastric, uterine and/or colon cancer), obesity linked gallbladderdisease, obesity linked inflammation, obesity induced sleep apnea,steatosis (fatty liver), glucagonomas, arteriosclerosis or heartfailure. In some embodiments the subject to which the ALK7 bindingprotein is administered is at risk of developing hypertension,dyslipidemia (for example, high total cholesterol or high levels oftriglycerides), type 2 diabetes, coronary heart disease, stroke,gallbladder disease, osteoarthritis, sleep disorders, respiratoryproblems, cancer (e.g., a myeloma (multiple myeloma, plasmacytoma,localized myeloma, or extramedullary myeloma), or an ovarian, breast,colon, endometrial, liver, kidney, pancreatic, gastric, uterine or coloncancer), obesity linked gallbladder disease, obesity linkedinflammation, obesity induced sleep apnea, steatosis, glucagonomas,arteriosclerosis or heart failure. In one embodiment, the administeredALK7-binding protein is an ALK7 antagonist. In one embodiment, theadministered antagonist ALK7-binding protein is an anti-ALK7 antibody oran ALK7-binding antibody fragment. In another embodiment theadministered antagonist ALK7-binding protein is an anti-ALK7 antibody oran ALK7-binding antibody fragment disclosed herein. In one embodiment,the administered ALK7-binding protein comprises a VH and VL pairdisclosed in Table 1A. In another embodiment, the administeredALK7-binding protein cross-blocks or competes for binding to ALK7 withan antibody comprising a VH and a VL sequence pair disclosed in Table1A. In one embodiment, the administered ALK7-binding protein comprises aVH and VL pair disclosed in Table 3. In another embodiment, theadministered ALK7-binding protein cross-blocks or competes for bindingto ALK7 with an antibody comprising a VH and a VL sequence pairdisclosed in Table 3. In one embodiment, the administered ALK7-bindingprotein comprises a VH and VL pair disclosed in Table 1A, Table 1B, orTable 3. In another embodiment, the administered ALK7-binding proteincross-blocks or competes for binding to ALK7 with an antibody comprisinga VH and a VL sequence pair disclosed in Table 1A, Table 1B, or Table 3.

In one embodiment, the disclosure provides a method of treating orameliorating type II diabetes or a condition associated with type IIdiabetes, comprising administering to a diabetic subject an effectiveamount of an ALK7-binding protein (e.g., an antagonist ALK7 bindingprotein such as an antagonist anti-ALK7 antibody). In one embodiment,the disclosure provides a method of treating or ameliorating a conditionassociated with type II diabetes. In a further embodiment, the conditionis a member selected from: an eye condition (e.g., glaucoma, cataracts,and retinopathy), cardiovascular disease (e.g., hypertension,atherosclerosis, myocardial infarction, and stroke), hyperglycemia,peripheral neuropathy, and kidney disease (e.g., nephropathy). In anadditional embodiment, the subject is at risk of developing type IIdiabetes or a condition associated with type II diabetes. In anotherembodiment, the subject is at risk of developing an eye condition (e.g.,glaucoma, cataracts, and retinopathy), cardiovascular disease (e.g.,hypertension, atherosclerosis, myocardial infarction, disorderedfibrinolysis, and stroke), hyperglycemia, peripheral neuropathy, orkidney disease (e.g., nephropathy). In one embodiment, the administeredALK7-binding protein is an ALK7 antagonist. In one embodiment, theadministered antagonist ALK7-binding protein is an anti-ALK7 antibody oran ALK7-binding antibody fragment. In another embodiment theadministered antagonist ALK7-binding protein is an anti-ALK7 antibody oran ALK7-binding antibody fragment disclosed herein. In one embodiment,the administered ALK7-binding protein comprises a VH and VL pairdisclosed in Table 1A. In one embodiment, the administered ALK7-bindingprotein comprises a VH and VL pair disclosed in Table 3. In anotherembodiment, the administered ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH and a VLsequence pair disclosed in Table 1B or Table 3.

In one embodiment, the disclosure provides a method of treating orameliorating a metabolic disease or disorder or a condition associatedwith a metabolic disease or disorder, comprising administering to aneffective amount of an ALK7-binding protein (e.g., an antagonist ALK7binding protein such as an antagonist anti-ALK7 antibody) to a subjectin need thereof. In one embodiment the treated or ameliorated conditionis an alteration of lipid, lipoprotein or apolipoprotein metabolism. Inanother embodiment the embodiment, the metabolic condition is highplasma triglyceride levels, hypertension, dyslipidemia high fastingblood sugar, low HDL cholesterol levels. In another embodiment, thetreated or ameliorated condition is atherosclerosis, arteriosclerosis,or endothelial dysfunction. In one embodiment the treated or amelioratedcondition is chronic inflammation. In another embodiment the treated orameliorated condition is non-alcoholic fatty liver disease (e.g., fattyliver and/or NASH). In one embodiment, the administered ALK7-bindingprotein is an ALK7 antagonist. In one embodiment, the administeredantagonist ALK7-binding protein is an anti-ALK7 antibody or anALK7-binding antibody fragment. In another embodiment the administeredantagonist ALK7-binding protein is an anti-ALK7 antibody or anALK7-binding antibody fragment disclosed herein. In one embodiment, theadministered ALK7-binding protein comprises a VH and VL pair disclosedin Table 1A. In another embodiment, the administered ALK7-bindingprotein cross-blocks or competes for binding to ALK7 with an antibodycomprising a VH and a VL sequence pair disclosed in Table 1A. In oneembodiment, the administered ALK7-binding protein comprises a VH and VLpair disclosed in Table 1B or Table 3. In another embodiment, theadministered ALK7-binding protein cross-blocks or competes for bindingto ALK7 with an antibody comprising a VH and a VL sequence pairdisclosed in Table 1B or Table 3.

In one embodiment, the disclosure provides a method of treating orameliorating insulin resistance or a condition associated with insulinresistance, comprising administering an effective amount of anALK7-binding protein (e.g., an antagonist ALK7 binding protein such asan antagonist anti-ALK7 antibody) to a subject in need thereof. In afurther embodiment, the he treated or ameliorated condition isassociated with impaired glucose tolerance or hyperglycemia. In anotherembodiment, the treated or ameliorated condition is associated withhypertension or atherosclerosis. In another embodiment, the treated orameliorated condition is a member selected from the group consisting of:dyslipidemia, hyperlipidemia, hypercholesterolemia, low HDL serum level,high LDL serum level (e.g., LDL-C≥100 mg/dL, ≥130 mg/dL, ≥160 mg/dL),and hypertriglyceridemia (e.g., TG≥150 mg/dL, ≥160 mg/dL, ≥170 mg/dL).In one embodiment, the administered ALK7-binding protein is an ALK7antagonist. In one embodiment, the administered antagonist ALK7-bindingprotein is an anti-ALK7 antibody or an ALK7-binding antibody fragment.In another embodiment the administered antagonist ALK7-binding proteinis an anti-ALK7 antibody or an ALK7-binding antibody fragment disclosedherein. In one embodiment, the administered ALK7-binding proteincomprises a VH and VL pair disclosed in Table 1A. In another embodiment,the administered ALK7-binding protein cross-blocks or competes forbinding to ALK7 with an antibody comprising a VH and a VL sequence pairdisclosed in Table 1A. In one embodiment, the administered ALK7-bindingprotein comprises a VH and VL pair disclosed in Table 1B or Table 3. Inanother embodiment, the administered ALK7-binding protein crossblocks orcompetes for binding to ALK7 with an antibody comprising a VH and a VLsequence pair disclosed in Table 1B or Table 3.

In one embodiment, the disclosure provides a method of treating orameliorating a disease or disorder of the eyes, nervous system, kidney,lungs, and/or liver, or associated condition, comprising administeringto an effective amount of an ALK7-binding protein (e.g., an antagonistALK7 binding protein such as an antagonist anti-ALK7 antibody) to asubject in need thereof. In one embodiment, the treated or amelioratedcondition is inflammation. In one embodiment, the treated or amelioratedcondition is nephropathy (e.g., diabetic nephropathy), arteriosclerosisof the renal artery), or kidney failure. In a further embodiment, thetreated or ameliorated condition is chronic inflammation. In a furtherembodiment the treated or ameliorated condition inflammation of adiposetissue. In another embodiment, the treated or ameliorated condition isinflammation of the liver. In another embodiment the treated orameliorated condition is NAFLD (e.g., fatty liver and/or NASH). In someembodiments, the subject to which the ALK7 binding protein isadministered is at risk of developing a disease or disorder of thekidney, lungs, or liver. In some embodiments, the subject to which theALK7 binding protein is administered is at risk of developingnephropathy. In some embodiments, the subject to which the ALK7 bindingprotein is administered is at risk of developing nephropathy. In oneembodiment, the subject is at risk of developing chronic inflammation.In one embodiment, the subject is at risk of developing inflammation ofadipose tissue. In an additional embodiment, the subject is at risk ofdeveloping inflammation of the liver. In one embodiment, theadministered ALK7-binding protein is an ALK7 antagonist. In oneembodiment, the administered antagonist ALK7-binding protein is ananti-ALK7 antibody or an ALK7-binding antibody fragment. In anotherembodiment the administered antagonist ALK7-binding protein is ananti-ALK7 antibody or an ALK7-binding antibody fragment disclosedherein. In one embodiment, the administered ALK7-binding proteincomprises a VH and VL pair disclosed in Table 1A. In another embodiment,the administered ALK7-binding protein cross-blocks or competes forbinding to ALK7 with an antibody comprising a VH and a VL sequence pairdisclosed in Table 1A. In one embodiment, the administered ALK7-bindingprotein comprises a VH and VL pair disclosed in Table 1B or Table 3. Inanother embodiment, the administered ALK7-binding protein cross-blocksor competes for binding to ALK7 with an antibody comprising a VH and aVL sequence pair disclosed in Table 1B or Table 3.

In one embodiment, the disclosure provides a method of treating orameliorating a cardiovascular disease or disorder or a conditionassociated with a cardiovascular disease or disorder, comprisingadministering to an effective amount of an ALK7-binding protein (e.g.,an antagonist ALK7 binding protein such as an antagonist anti-ALK7antibody) to a subject in need thereof. In one embodiment, the treatedor ameliorated condition is coronary heart disease, congestive heartfailure, vascular restenosis, stroke, peripheral vascular disease,microvascular disease, disordered fibrinolysis, or arteriosclerosis. Inone embodiment, the subject to which the ALK7 binding protein isadministered is at risk of developing coronary heart disease, congestiveheart failure, vascular restenosis, stroke, peripheral vascular disease,microvascular disease, or arteriosclerosis. In one embodiment, thetreated or ameliorated condition is hypertension (e.g., bloodpressure>130/80 mmHg in a resting state). In one embodiment, the subjectto which the ALK7 binding protein is administered is at risk ofdeveloping hypertension. In one embodiment, the treated or amelioratedcondition is atherosclerosis. In one embodiment, the subject to whichthe ALK7 binding protein is administered is at risk of developingatherosclerosis. In one embodiment, the administered ALK7-bindingprotein is an ALK7 antagonist. In one embodiment, the administeredantagonist ALK7-binding protein is an anti-ALK7 antibody or anALK7-binding antibody fragment. In another embodiment the administeredantagonist ALK7-binding protein is an anti-ALK7 antibody or anALK7-binding antibody fragment disclosed herein. In one embodiment, theadministered ALK7-binding protein comprises a VH and VL pair disclosedin Table 1A. In another embodiment, the administered ALK7-bindingprotein cross-blocks or competes for binding to ALK7 with an antibodycomprising a VH and a VL sequence pair disclosed in Table 1A. In oneembodiment, the administered ALK7-binding protein comprises a VH and VLpair disclosed in Table 1B. In another embodiment, the administeredALK7-binding protein cross-blocks or competes for binding to ALK7 withan antibody comprising a VH and a VL sequence pair disclosed in Table1B. In one embodiment, the administered ALK7-binding protein comprises aVH and VL pair disclosed in Table 3. In another embodiment, theadministered ALK7-binding protein cross-blocks or competes for bindingto ALK7 with an antibody comprising a VH and a VL sequence pairdisclosed in Table 3.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

FIG. 1 shows the amount of adipose change in TBS and ALK7 mAb treatedhigh-fat diet (HFD) mice. Changes in the amount of adipose are relativeto baseline prior to ALK7 Ab or TBS treatment. Treatment with ALK7 mAbs(i.e., J02, K02, G05, C03, and L02) significantly reduced fat mass inHFD mice. * designates p>0.001 vs. HFD+TBS.

FIG. 2 shows the amount of lean body mass change in TBS and ALK7 mAbtreated high-fat diet (HFD) mice. Changes in the amount of lean mass arerelative to baseline prior to ALK7 Ab or TBS treatment. Treatment withALK7 mAbs (i.e., J02, K02, G05, C03, and L02) did not change lean bodymass in HFD mice.

DETAILED DESCRIPTION

The disclosure provides isolated and/or recombinant ALK7-bindingproteins. In certain embodiments the ALK7-binding proteins specificallybind ALK7. In further embodiments, the ALK7-binding proteins areanti-ALK7 antibodies. Nucleic acids encoding the ALK7-binding proteins,vectors and host cells containing the nucleic acids, and methods ofmaking and using the ALK7-binding proteins are also provided. Theprovided ALK7-binding proteins have uses in diagnosing, treating, and/orameliorating diseases and conditions associated with increased ALK7expression and/or signaling. Such uses include but are not limited to,preventing, and/or ameliorating obesity (e.g., abdominal obesity);overweight; insulin resistance; metabolic syndrome and other metabolicdiseases or conditions; a lipid disorder such as, low HDL levels, highLDL levels, hyperlipidemia, hypertriglyceridemia or dyslipidemia;lipoprotein aberrations; decreased triglycerides; inflammation (e.g.,liver inflammation and/or inflammation of adipose tissue), fatty liverdisease; non-alcoholic fatty liver disease; hyperglycemia; impairedglucose tolerance (IGT); hyperinsulinemia; high cholesterol (e.g., highLDL levels and hypercholesterolemia); cardiovascular disease such as,heart disease including coronary heart disease, congestive heartfailure, stroke, peripheral vascular disease, atherosclerosis;arteriosclerosis, and hypertension; Syndrome X; vascular restenosis;neuropathy; retinopathy; neurodegenerative disease; endothelialdysfunction, respiratory dysfunction, renal disease (e.g., nephropathy);pancreatitis; polycystic ovarian syndrome; elevated uric acid levels;haemochromatosis (iron overload); acanthosis nigricans (dark patches onthe skin); and cancer (e.g., a myeloma (multiple myeloma, plasmacytoma,localized myeloma, or extramedullary myeloma), or an ovarian, breast,colon, endometrial, liver, kidney, pancreatic, gastric, uterine and/orcolon cancer); and other disorders/conditions associated with one ormore of the above diseases or conditions, or with overweight (e.g., BMIof 25 kg/m²), or too much body fat.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure is related. For example, the ConciseDictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed.,2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed.,1999, Academic Press; and the Oxford Dictionary Of Biochemistry AndMolecular Biology, Revised, 2000, Oxford University Press, provide oneof skill with a general dictionary of many of the terms used in thisdisclosure. The headings provided herein are not limitations of thevarious embodiments which can be had by reference to the specificationas a whole. Moreover, the terms defined immediately below are more fullydefined by reference to the specification in its entirety.

The terms “a,” “an” and “the” include plural referents unless thecontext in which the term is used clearly dictates otherwise. The terms“a” (or “an”), as well as the terms “one or more,” and “at least one”can be used interchangeably herein. Furthermore, “and/or” where usedherein is to be taken as specific disclosure of each of the two or morespecified features or components with or without the other. Thus, theterm “and/or” as used in a phrase such as “A and/or B” herein isintended to include “A and B,” “A or B,” “A” (alone), and “B” (alone).Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C”is intended to encompass each of the following embodiments: A, B, and C;A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A(alone); B (alone); and C (alone).

The term “comprise” is generally used in the sense of include, that isto say permitting the presence of one or more features or components.Wherever embodiments are described herein with the language“comprising,” otherwise analogous embodiments described in terms of“consisting of,” and/or “consisting essentially of” are also provided.

The terms “about” and “approximately” as used in connection with anumerical value throughout the specification and the claims denotes aninterval of accuracy, familiar and acceptable to a person skilled in theart. In general, such interval of accuracy is ±10%. Alternatively, andparticularly in biological systems, the terms “about” and“approximately” may mean values that are within an order of magnitude,preferably ≤5-fold and more preferably ≤2-fold of a given value.

Numeric ranges are inclusive of the numbers defining the range.

An ALK7-binding protein refers to a protein that specifically binds toALK7, preferably binding to the extracellular domain of ALK7.

The terms “ALK7” and “ALK7 receptor” are used interchangeably and referto ALK7 (also referred to as ACVRLK7, Activin A Receptor, Type IC,ACVR-1C, Activin Receptor-Like kinase 7, and EC 2.7.11 in theliterature). Reference sequence for human ALK7 is provided in NCBIReference Sequences NP_001104501.1. The provided ALK7-binding proteinsbind the extracellular domain of human ALK7 corresponding to the aminoacid sequence of SEQ ID NO:86. Reference sequence for rat ALK7 isprovided in NCBI Reference Sequences P70539. In some embodiments, theprovided ALK7-binding proteins bind the extracellular domain of rat ALK7corresponding to the amino acid sequence of SEQ ID NO:87.

The term “compete” or “competes” when used in the context ofALK7-binding proteins (e.g., neutralizing antibodies) means competitionbetween antigen binding proteins as determined by an assay in which theantigen binding protein (e.g., an anti-ALK7 antibody or an ALK7-bindingfragment thereof) under test prevents or inhibits specific binding of areference antigen binding protein (e.g., a ligand, or a referenceantibody) to a common antigen (e.g., an ALK7 extracellular domain or afragment thereof). Numerous types of competitive binding assays can beused, for example: solid phase direct or indirect radioimmunoassay (RIA)(see, e.g., Moldenhauer et al., Scand. J. Immunol. 32:77-82 (1990) andMorel et al., Molec. Immunol. 25:7-15 (1988)), solid phase direct orindirect enzyme immunoassay (EIA), solid phase direct biotin-avidin EIA(see, e.g., Cheung, et al., Virology 176:546-552 (1990) and Kirkland etal., J. Immunol. 137:3614-3619 (1986)) and a sandwich competition assay(see, e.g., Stahli et al., Methods in Enzymology 92:242-253 (1983)).Typically, such an assay involves the use of purified antigen bound to asolid surface or cells bearing either of these, an unlabeled testantigen binding protein and a labeled reference antigen binding protein.

Competitive inhibition can be measured by determining the amount oflabel bound to the solid surface or cells in the presence of the testantigen binding protein. Usually the test antigen binding protein ispresent in excess. Antigen binding proteins identified by competitionassay (competing antigen binding proteins) include ALK7-binding proteinsthat bind to the same epitope as the reference ALK7-binding protein aswell as ALK7-binding proteins that bind to an adjacent epitopesufficiently proximal to the epitope bound by the reference ALK7-bindingprotein for steric hindrance to occur. Usually, when a competing ALK7binding protein is present in excess, it will inhibit specific bindingof a reference ALK7-binding protein to ALK7 by at least 40%, 45%, 50%,55%, 60%, 65%, 70% or 75%. In some instance, a competing antigen bindingprotein inhibits specific binding of a reference ALK7-binding protein byat least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, or 99%.

The term “epitope” when used in context of an ALK7 protein refers to anALK7 (e.g., human ALK7 or murine ALK7) protein determinant capable ofbinding to an ALK7-binding protein (e.g., an antibody) of thedisclosure. Epitopes usually consist of chemically active surfacegroupings of molecules such as amino acids or sugar side chains andusually have specific three-dimensional structural characteristics, aswell as specific charge characteristics. Conformational andnon-conformational epitopes are distinguished in that the binding to theformer but not the latter is lost in the presence of denaturingsolvents. The ALK7 epitope bound by an ALK7-binding protein can readilybe determined using techniques known in the art.

Antigen binding proteins such as the anti-ALK7-binding antibodies andALK7-binding fragments, variants, or derivatives thereof disclosedherein, can be described or specified in terms of the epitope(s) orportion(s) of an antigen, e.g., a target polypeptide that they recognizeor specifically bind. For example, the portion of ALK7 that specificallyinteracts with the antigen binding domain of an ALK7-binding proteindisclosed herein is an “epitope.” Epitopes can be formed both fromcontiguous amino acids or noncontiguous amino acids juxtaposed bytertiary folding of a protein. Epitopes formed from contiguous aminoacids are typically retained on exposure to denaturing solvents, whereasepitopes formed by tertiary folding are typically lost on treatment withdenaturing solvents. Epitope determinants may include chemically activesurface groupings of molecules such as amino acids, sugar side chains,phosphoryl or sulfonyl groups, and may have specific three dimensionalstructural characteristics, and/or specific charge characteristics. Anepitope typically includes at least 3, 4, 5, 6, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35 amino acids in aunique spatial conformation. Epitopes can routinely be determined usingmethods known in the art.

The terms “inhibit,” “block,” “reduce,” “decrease,” “suppress,”“antagonize,” and “neutralize” are used interchangeably and refer to anystatistically significant decrease in activity (e.g., ALK7 ligandbinding and/or ALK7 signaling), including full blocking of the activity.For example, “inhibition,” “suppression,” or “antagonize” can refer to adecrease of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% inactivity compared to a control.

In some embodiments, the term “decrease,” “inhibit,” or “antagonize” mayrefer to the ability of an ALK7-binding protein such as an antibody orALK7-binding fragment thereof, to statistically significantly (e.g.,with a p value less than or equal to 0.05) decrease the phosphorylationof one or more Smads (e.g., Smad2 and/or Smad3) induced by contacting acell expressing ALK7 and ActrIIA/B with an ALK7 ligand such as, GDF1,GDF3, GDF8, activin B, activin A/B, and/or Nodal, relative to the extentof Smad phosphorylation in the cell when not contacted with theALK7-binding protein. The cell which expresses ALK7 can be a naturallyoccurring cell or a cell line, or can be recombinantly produced byintroducing a nucleic acid encoding ALK7 into a host cell. In oneembodiment, the ALK7-binding protein, e.g., an ALK7 antibody orALK7-binding fragment thereof, antagonizes (decreases) ALK7 ligandmediated phosphorylation of one or more Smads (e.g., Smad2 and/or Smad3)by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or byabout 100%, as determined, for example, by Western blotting followed byprobing with an anti-phosphotyrosine antibody or by ELISA (e.g., P-SmadELISA) or a Smad dependent reporter gene assay using techniquesdescribed herein or otherwise known in the art. In one embodiment, theALK7-binding protein, antagonizes (decreases) ALK7-mediated inhibitionof lipolysis in adipose cells. In one embodiment, an ALK7-bindingprotein is an ALK7 antagonist and antagonizes ALK7-mediated inhibitionof lipolysis in white adipose cell by 5% to 100%, 10% to 95%, 10 to 90%,10 to 85%, 10 to 80%, 10 to 75%, 10 to 70%, 10 to 75%, 10 to 70%, 10 to60%, 10 to 55%, 10 to 50%, or 10 to 45%, as determined in a lipolysisassay. In another embodiment, an ALK7-binding protein reduces ordecreases ALK7-mediated inhibition of lipolysis in white adipose cellsby at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, orby about 100%, as determined in a lipolysis assay. In some embodimentsthe lipolysis assay is performed in the presence of one or more ALK7ligands. In further embodiments, the lipolysis assay is performed in thepresence of one or more ALK7 ligands selected from the group consistingof GDF1, GDF3, GDF8, activin B, activin A/B, and Nodal).

In one embodiment, an ALK7-binding protein is an ALK7 antagonist andantagonizes ALK7-mediated inhibition of lipolysis in white and/or brownadipose cells by 5% to 100%, 10% to 95%, 10 to 90%, 10 to 85%, 10 to80%, 10 to 75%, 10 to 70%, 10 to 75%, 10 to 70%, 10 to 60%, 10 to 55%,10 to 50%, or 10 to 45%, as determined in a lipolysis assay. In anotherembodiment, an ALK7-binding protein reduces or decreases ALK7-mediatedinhibition of lipolysis in white and/or brown adipose cells by at least5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 950, or by about100%, as determined in a lipolysis assay. In some embodiments thelipolysis assay is performed in the presence of one or more ALK7ligands. In further embodiments, the lipolysis assay is performed in thepresence of one or more ALK7 ligands selected from the group consistingof GDF1, GDF3, GDF8, activin B, activin A/B, and Nodal).

The terms “increase,” “promote” and “agonist” are used interchangeablyand refer to any statistically significant increase in activity (e.g.,ALK7 ligand binding and/or ALK7 signaling). For example, “increase” or“promote” can refer to an increase of about 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90% or 100% in activity compared to a control.

In some embodiments, the ALK7-binding protein increases lipolysis incells. In some embodiments, the ALK7-binding protein increases lipolysisin cells by at least 5% to 100%, 10% to 95%, 10 to 90%, 10 to 85%, 10 to80%, 10 to 75%, 10 to 70%, 10 to 75%, 10 to 70%, 10 to 60%, 10 to 55%,10 to 50%, or 10 to 45%, as determined in a lipolysis assay. In someembodiments, the ALK7-binding protein increases lipolysis in adiposecells. In some embodiments, the ALK7-binding protein increases lipolysisin adipose cells by at least 5% to 100%, 10% to 95%, 10 to 90%, 10 to85%, 10 to 80%, 10 to 75%, 10 to 70%, 10 to 75%, 10 to 70%, 10 to 60%,10 to 55%, 10 to 50%, or 10 to 45%, as determined in a lipolysis assay.In some embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands. In further embodiments, the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of GDF1, GDF3, GDF8, activin B, activin A/B, and Nodal.In some embodiments, the ALK7-binding protein increases lipolysis inwhite adipose cells or brown adipose cells.

In some embodiments, the ALK7-binding protein increases lipolysis inwhite adipose cells. In some embodiments, the ALK7-binding proteinincreases lipolysis in white adipose cells by at least 5% to 100%, 10%to 95%, 10 to 90%, 10 to 85%, 10 to 80%, 10 to 75%, 10 to 70%, 10 to75%, 10 to 70%, 10 to 60%, 10 to 55%, 10 to 50%, or 10 to 45%, asdetermined in a lipolysis assay. In some embodiments the lipolysis assayis performed in the presence of one or more ALK7 ligands. In furtherembodiments, the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal.

In some embodiments, the ALK7-binding protein increases lipolysis inbrown adipose cells. In some embodiments, the ALK7-binding proteinincreases lipolysis in brown adipose cells by at least 5% to 100%, 10%to 95%, 10 to 90%, 10 to 85%, 10 to 80%, 10 to 75%, 10 to 70%, 10 to75%, 10 to 70%, 10 to 60%, 10 to 55%, 10 to 50%, or 10 to 45%, asdetermined in a lipolysis assay. In some embodiments the lipolysis assayis performed in the presence of one or more ALK7 ligands. In furtherembodiments, the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal.

In some embodiments, the ALK7-binding protein increases lipolysis inwhite and brown adipose cells. In some embodiments, the ALK7-bindingprotein increases lipolysis in white and brown adipose cells by at least5% to 100%, 10% to 95%, 10 to 90%, 10 to 85%, 10 to 80%, 10 to 75%, 10to 70%, 10 to 75%, 10 to 70%, 10 to 60%, 10 to 55%, 10 to 50%, or 10 to45%, as determined in a lipolysis assay. In some embodiments thelipolysis assay is performed in the presence of one or more ALK7ligands. In further embodiments, the lipolysis assay is performed in thepresence of one or more ALK7 ligands selected from the group consistingof GDF1, GDF3, GDF8, activin B, activin A/B, and Nodal.

In an additional embodiment, an ALK7-binding protein increases lipolysisin white adipose cells by at least 5% to 100%, 10% to 95%, 10 to 90%, 10to 85%, 10 to 80%, 10 to 75%, 10 to 70%, 10 to 75%, 10 to 70%, 10 to60%, 10 to 55%, 10 to 50%, or 10 to 45%, as determined using standardtechniques and conditions in a lipolysis assay performed in the presenceof activin B (50 ng/ml) (e.g., as described in the examples herein). Inanother embodiment, an ALK7-binding protein reduces or decreasesALK7-mediated inhibition of lipolysis in white adipose cells by at least5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or by about1000, as determined, using standard techniques and conditions in alipolysis inhibition assay. the lipolysis assay is performed in thepresence of activin B (50 ng/ml) (e.g., as described in the examplesherein).

In an additional embodiment, an ALK7-binding protein increases lipolysisin white and/or brown adipose cells by at least 5% to 100%, 10% to 95%,10 to 90%, 10 to 85%, 10 to 80%, 10 to 75%, 10 to 70%, 10 to 75%, 10 to70%, 10 to 60%, 10 to 55%, 10 to 50%, or 10 to 45%, as determined usingstandard techniques and conditions in a lipolysis assay performed in thepresence of activin B (50 ng/ml) (e.g., as described in the examplesherein). In another embodiment, an ALK7-binding protein reduces ordecreases ALK7-mediated inhibition of lipolysis in white adipose cellsby at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, orby about 100%, as determined, using standard techniques and conditionsin a lipolysis inhibition assay. the lipolysis assay is performed in thepresence of activin B (50 ng/ml) (e.g., as described in the examplesherein).

In some embodiments, the ALK7-binding protein increases glycerolproduction in adipose cells. In some embodiments, the ALK7-bindingprotein increases glycerol production in adipose cells by at least 5% to100%, 10% to 95%, 10 to 90%, 10 to 85%, 10 to 80%, 10 to 75%, 10 to 70%,10 to 75%, 10 to 70%, 10 to 60%, 10 to 55%, 10 to 50%, or 10 to 45%, asdetermined in a lipolysis assay. In some embodiments the lipolysis assayis performed in the presence of one or more ALK7 ligands. In someembodiments, the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein increases glycerol production in white adiposecells or brown adipose cells.

The terms “antibody” and “immunoglobulin,” are used interchangeablyherein, and include whole (full-length) antibodies and antigen bindingfragment or single chains thereof. A typical antibody comprises at leasttwo heavy (H) chains and two light (L) chains interconnected bydisulfide bonds. Each heavy chain is comprised of a heavy chain variableregion (abbreviated herein as VH) and a heavy chain constant region. Theheavy chain constant region is comprised of three domains, CH1, CH2, andCH3. Each light chain is comprised of a light chain variable region(abbreviated herein as VL) and a light chain constant region. The lightchain constant region is comprised of one domain, CL. The VH and VLregions can be further subdivided into regions of hypervariability,termed Complementarity Determining Regions (CDR), interspersed withregions that are more conserved, termed framework regions (FW). Each VHand VL is composed of three CDRs and four FWs, arranged fromamino-terminus to carboxy-terminus in the following order: FW1, CDR1,FW2, CDR2, FW3, CDR3, FW4. The variable regions of the heavy and lightchains contain a binding domain that interacts with an antigen. Theconstant regions of the antibodies can mediate the binding of theimmunoglobulin to host tissues or factors, including various cells ofthe immune system (e.g., effector cells) and the first component (Clq)of the classical complement system. Exemplary antibodies include typicalantibodies, scFvs, and combinations thereof where, for example, an scFvis covalently linked (for example, via peptidic bonds or via a chemicallinker) to the N or C-terminus of either the heavy chain and/or thelight chain of a typical antibody, or intercalated in the heavy chainand/or the light chain of a typical antibody.

The terms “antibody” and “immunoglobulin,” encompass intact polyclonalantibodies, intact monoclonal antibodies, antibody fragments (such asFab, Fab′, F(ab′)2, and Fv fragments), single chain Fv (scFv)derivatives and mutants, multispecific antibodies such as bispecificantibodies, chimeric antibodies, humanized antibodies, human antibodies,fusion proteins comprising an antigen determination portion of anantibody, and any other modified immunoglobulin molecule comprising anantigen recognition site so long as the antibodies exhibit the desiredbinding activity. An antibody can be of any the five major classes ofimmunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes)thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), based on theidentity of their heavy-chain constant domains referred to as alpha,delta, epsilon, gamma, and mu, respectively. The different classes ofimmunoglobulins have different and well known subunit structures andthree-dimensional configurations. Antibodies can be naked or conjugatedto other molecules such as toxins, radioisotopes, etc. The term “IgG”refers to a polypeptide belonging to the class of antibodies that aresubstantially encoded by a recognized immunoglobulin gamma gene. Inhumans this class comprises IgG1, IgG2, IgG3, and IgG4. In mice thisclass comprises IgG1, IgG2a, IgG2b, and IgG3.

The terms “ALK7 antibody,” “an antibody that binds to ALK7,” or“anti-ALK7 antibody” refer to an antibody that is capable of bindingALK7 with sufficient affinity such that the antibody is useful as atherapeutic agent or diagnostic reagent in targeting ALK7, respectively.

By “specifically binds” when used in the context of ALK7 proteins, it isgenerally meant the ability of a binding protein such as an antibody, tobind to ALK7 (e.g., human ALK7, preferably an extracellular domain ofALK7), with greater affinity than the binding protein binds to anunrelated control protein. In some embodiments, the control protein ishen egg white lysozyme. Preferably the binding protein binds ALK7 withan affinity that is at least, 100, 500, or 1000 times greater than theaffinity for a control protein. Preferably, the binding protein has abinding affinity for human ALK7 of ≤1×10⁻⁷ M or ≤1×10⁻⁸ as measuredusing a binding assay known in the art. In some embodiments, the bindingaffinity is measured using a radioimmunoassay (RIA) or BIACORE® (e.g.,using ALK7 as the analyte and ALK7-binding protein as the ligand, orvice versa).

In some embodiments, the extent of binding of an ALK7-binding protein(e.g., an anti-ALK7 antibody) to an unrelated, non-ALK7 protein is lessthan about 10% of the binding of the ALK7-binding protein to ALK7 asmeasured, for example, by a radioimmunoassay (RIA), BIACORE® (usingrecombinant ALK7 as the analyte and ALK7-binding protein as the ligand,or vice versa), kinetic exclusion assay (KINEXA®), or other bindingassays known in the art. In certain embodiments, the ALK7-bindingprotein is a full-length antibody or an ALK7-binding antibody fragmentthat has a dissociation constant (K_(D)) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1nM, ≤0.1 nM, ≤10 pM, ≤1 pM, or ≤0.1 pM.

The term “antigen binding antibody fragment” (e.g., “ALK7-bindingantibody fragment”) refers to a fragment containing all or a portion ofan antigen binding variable region (e.g., CDR3) of an intact antibody.It is known that the antigen binding function of an antibody can beperformed by fragments of a full-length antibody. Examples of antibodyfragments include, but are not limited to Fab, Fab′, F(ab′)2, and Fvfragments, linear antibodies, single chain antibodies, and multispecificantibodies formed from one or more antibody fragments. In someembodiments the disclosure provides ALK7-binding antibody fragmentswherein the antibody fragment is a Fab fragment, a Fab′ fragment, aF(ab′)₂ fragment, a Fv fragment, a diabody, or a single chain antibodymolecule.

The Fc region includes polypeptides comprising the constant region of anantibody excluding the first constant region immunoglobulin domain.Thus, Fc refers to the last two constant region immunoglobulin domainsof IgA, IgD, and IgG, and the last three constant region immunoglobulindomains of IgE and IgM, and the flexible hinge N-terminal to thesedomains. For IgA and 1 μM Fc may include the J chain. For IgG, Fecomprises immunoglobulin domains Cγ2 and Cγ3 and the hinge between Cγ1and Cγ2. Although the boundaries of the Fe region may vary, the humanIgG heavy chain Fc region is usually defined to comprise residues C226or P230 to its carboxyl-terminus, wherein the numbering is according tothe EU index as set forth in Kabat (Kabat et al., Sequences of Proteinsof Immunological Interest, 5th Ed. Public Health Service, NIH, Bethesda,Md. (1991)). Fc may refer to this region in isolation, or this region inthe context of a whole antibody, antibody fragment, or Fc fusionprotein. Polymorphisms have been observed at a number of different Fcpositions, including but not limited to positions 270, 272, 312, 315,356, and 358 as numbered by the EU index, and thus slight differencesbetween the presented sequence and sequences in the prior art may exist.

A “monoclonal antibody” refers to a homogeneous antibody populationinvolved in the highly specific recognition and binding of a singleantigenic determinant or epitope. This is in contrast to polyclonalantibodies that typically include different antibodies directed againstdifferent antigenic determinants. The term “monoclonal antibody”encompasses both intact and full-length monoclonal antibodies as well asantibody fragments (such as Fab, Fab′, F(ab′)2, and Fv), single chain(scFv) mutants, and fusion proteins) comprising an antibody portion, andany other modified immunoglobulin molecule comprising an antigenrecognition site. A monoclonal antibody may be made in any number ofways including, but not limited to, by hybridoma, phage selection,recombinant expression, and transgenic animals.

The term “chimeric antibody” refers to an antibody wherein the aminoacid sequence of the immunoglobulin molecule is derived from two or morespecies. Typically, the variable region of both light and heavy chainscorresponds to the variable region of antibodies derived from onespecies of mammal (e.g., mouse, rat, rabbit, etc.) with the desiredantigen-binding specificity, affinity, and/or capability while theconstant regions are homologous to the sequences in antibodies derivedfrom another species (usually human) to avoid eliciting an immuneresponse in that species.

The term “humanized antibody” refers to an antibody derived from anon-human (e.g., murine) immunoglobulin, which has been engineered tocontain fewer preferably minimal non-human (e.g., murine) sequences.Typically, humanized antibodies are human immunoglobulins in whichresidues from the CDR are replaced by residues from the CDR of anon-human species (e.g., mouse, rat, rabbit, or hamster) that have thedesired antigen-binding specificity, affinity, and/or capability (Jones,Nature 321:522-525 (1986); Riechmann, Nature 332:323-327 (1988);Verhoeyen, Science 239:1534-1536 (1988)). In some instances, the Fvframework region (FW) residues of a human immunoglobulin are replacedwith the corresponding residues in an antibody from a non-human speciesthat has the desired antigen-binding specificity, affinity, and/orcapability. The humanized antibody can be further modified by thesubstitution of additional residues either in the Fv framework regionand/or within the replaced non-human residues to refine and optimizeantibody specificity, affinity, and/or capability. In general, thehumanized antibody will comprise substantially all of at least one, andtypically two or three, variable domains containing all or substantiallyall of the CDR regions that correspond to the non-human immunoglobulinwhereas all or substantially all of the FR regions are those of a humanimmunoglobulin consensus sequence. The humanized antibody can alsocomprise at least a portion of an immunoglobulin constant region ordomain (Fc), typically that of a human immunoglobulin. Examples ofmethods used to generate humanized antibodies are described in U.S. Pat.Nos. 5,225,539 and 5,639,641.

The term “human antibody” refers to an antibody produced by a human oran antibody having an amino acid sequence corresponding to an antibodyproduced by a human made using any technique known in the art. The term“human antibody” includes intact (full-length) antibodies, fragmentsthereof, and/or antibodies comprising at least one human heavy and/orlight chain polypeptide such as, an antibody comprising murine lightchain and human heavy chain polypeptides.

An “antagonist,” “blocking,” or “neutralizing” binding protein is onethat inhibits or reduces activity of the antigen it binds, such as ALK7.In some embodiments, the antagonist ALK7-binding protein reduces orinhibits the multimerization of ALK7, and ActRII receptor (e.g., ActRIIAor ActRIIB) an GDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal.In certain embodiments the antagonist ALK7-binding protein substantiallyor completely inhibits the activity of the ALK7. In some embodiments,the ALK7 activity is reduced by 10%, 20%, 30%, 50%, 70%, 80%, 90%, 95%,or 100%. In certain embodiments the antagonist ALK7-binding protein isan anti-ALK7 antibody, such as a full-length antibody or an ALK7-bindingantibody fragment. In further embodiments, the antagonist anti-ALK7antibody inhibits or reduces the activity of ALK7 by at least 10%, 20%,30%, 50%, 70%, 80%, 90%, 95%, or even 100%.

“Binding affinity” generally refers to the strength of the sum total ofnon-covalent interactions between a single binding site of a molecule(e.g., an antibody) and its binding partner (e.g., an antigen). Unlessindicated otherwise, “binding affinity” refers to intrinsic bindingaffinity which reflects a 1:1 interaction between members of a bindingpair (e.g., antibody and antigen). The affinity of a molecule X for itspartner Y can generally be represented by the dissociation constant(K_(D)). Affinity can be measured by common methods known in the art,including those described herein and can be used for the purposes of thepresent disclosure.

“Potency” is a measure of pharmacological activity of a compoundexpressed in terms of the amount of the compound required to produce aneffect of given intensity. It refers to the amount of the compoundrequired to achieve a defined biological effect; the smaller the doserequired, the more potent the drug. Potency is normally expressed as anIC₅₀ value, in nM unless otherwise stated. IC₅₀ is the median inhibitoryconcentration of an ALK7-binding protein (e.g., an anti-ALK7 antibody).In functional assays, IC₅₀ is the concentration that reduces abiological response by 50% of its maximum. In ligand-receptor bindingstudies, IC₅₀ is the concentration that reduces ligand-receptor bindingby 50% of maximal specific binding level. IC₅₀ can be calculated by anynumber of means known in the art. The fold improvement in potency forthe antibodies or other binding protein provided herein as compared to areference anti-ALK7 antibody or other ALK7-binding protein can be atleast 2-fold, 4-fold, 6-fold, 8-fold, 10-fold, 20-fold, 30-fold,40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold,110-fold, 120-fold, 130-fold, 140-fold, 150-fold, 160-fold, 170-fold, orat least 180-fold.

“Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to aform of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs)present on certain cytotoxic cells (e.g., Natural Killer (NK) cells,neutrophils, and macrophages) enables these cytotoxic effector cells tobind specifically to an antigen-bearing target cell and subsequentlykill the target cell with cytotoxins. Specific high-affinity IgGantibodies directed to the surface of target cells “arm” the cytotoxiccells and are absolutely required for such killing. Lysis of the targetcell is extracellular, requires direct cell-to-cell contact, and doesnot involve complement. It is contemplated that, in addition toantibodies, other proteins comprising Fc regions, specifically Fc fusionproteins, having the capacity to specifically bind to an ALK7-bearingtarget cell will be able to effect cell-mediated cytotoxicity. Forsimplicity, the cell-mediated cytotoxicity resulting from the activityof an Fc fusion protein is also referred to herein as ADCC activity.

An ALK7-binding protein (e.g., an ALK7 antibody, including anALK7-binding fragment, variant, and derivative thereof), polynucleotide,vector, cell, or composition which is “isolated” is a protein (e.g.,antibody), polynucleotide, vector, cell, or composition which is in aform not found in nature. Isolated proteins, polynucleotides, vectors,cells or compositions include those which have been purified to a degreethat they are no longer in a form in which they are found in nature. Insome embodiments, a protein, polynucleotide, vector, cell, orcomposition which is isolated is substantially pure. Isolated proteinsand isolated nucleic acid will be free or substantially free of materialwith which they are naturally associated such as other polypeptides ornucleic acids with which they are found in their natural environment, orthe environment in which they are prepared (e.g., cell culture) whensuch preparation is by recombinant DNA technology practiced in vitro orin vivo. Proteins and nucleic acid may be formulated with diluents oradjuvants and still for practical purposes be isolated—for example theproteins will normally be mixed with gelatin or other carriers if usedto coat microtitre plates for use in immunoassays, or will be mixed withpharmaceutically acceptable carriers or diluents when used in diagnosisor therapy.

The terms “subject,” “individual,” “animal,” “patient,” and “mammal,”refer to any subject, particularly a mammalian subject, for whomdiagnosis, prognosis, or therapy is desired. Mammalian subjects includebut are not limited to humans, non-human primates, domestic animals,farm animals, rodents, and the like, which is to be the recipient of aparticular treatment.

The term “pharmaceutical composition” refers to a preparation which isin such form as to permit the biological activity of the activeingredient to be effective, and which contains no additional componentsat concentrations that are unacceptably toxic to a subject to which thecomposition would be administered. Such composition can be sterile.

An “effective amount” of a polypeptide, e.g., an antigen binding proteinincluding an antibody, as disclosed herein is an amount sufficient tocarry out a specifically stated purpose. An “effective amount” can bedetermined empirically and in a routine manner, in relation to thestated purpose. The term “therapeutically effective amount” refers to anamount of a polypeptide, e.g., an antigen binding protein including anantibody, or other drug effective to “treat” a disease or condition in asubject (e.g., a mammal such as a human) and provides some improvementor benefit to a subject having the disease or condition. Thus, a“therapeutically effective” amount is an amount that provides somealleviation, mitigation, and/or decrease in at least one clinicalsymptom of an ALK7-mediated disease or condition. Clinical symptomsassociated with the diseases or conditions that can be treated by themethods of the disclosure are well known. Further, therapeutic effectsneed not be complete or curative, as long as some benefit is provided tothe subject. In some embodiments, the term “therapeutically effective”refers to an amount of a therapeutic agent that is capable of reducingALK7 activity in a subject in need thereof. The actual amountadministered and rate and time-course of administration, will depend onthe nature and severity of what is being treated. Prescription oftreatment, e.g., decisions on dosage etc., is within the responsibilityof general practitioners and other medical doctors. Appropriate doses ofantibodies and antigen binding fragments thereof are generally known;see, Ledermann et al., Int. J. Cancer 47:659-664 (1991); Bagshawe etal., Ant. Immun. and Radiopharm. 4:915-922 (1991).

A “sufficient amount” or “an amount sufficient to” achieve a particularresult in a subject having an ALK7-mediated disease or condition refersto an amount of a therapeutic agent (e.g., an antigen binding proteinincluding an antibody, as disclosed herein) that is effective to producea desired effect, which is optionally a therapeutic effect (i.e., byadministration of a therapeutically effective amount). In someembodiments, such particular result is a reduction in ALK7 activity in asubject in need thereof.

The term “label” refers to a detectable compound or composition which isconjugated directly or indirectly to a moiety such as an anti-ALK7antibody so as to generate a “labeled” moiety. The label can bedetectable by itself (e.g., radioisotope labels or fluorescent labels)or, in the case of an enzymatic label, can catalyze chemical alterationof a substrate compound or composition which is detectable.

Terms such as “treating,” or “treatment,” “to treat” or “ameliorating”and “to ameliorate” refer to both (a) therapeutic measures that cure,slow down, lessen symptoms of, and/or halt progression of a diagnosedpathologic condition or disorder and (b) prophylactic or preventativemeasures that prevent and/or slow the development of a targeted diseaseor condition. Thus, subjects in need of treatment include those alreadywith the disease or condition; those at risk of developing the diseaseor condition; and those in whom the disease or condition is to beprevented. In certain embodiments, a subject is successfully “treated”according to the methods provided herein if the subject shows, e.g.,total, partial, or transient amelioration or elimination of a symptomassociated with the disease or condition. In some embodiments, thedisclosure provides a method for treating a disease, disorder orcondition selected from, obesity (e.g., abdominal obesity); insulinresistance; metabolic syndrome and other metabolic diseases orconditions; a lipid disorder such as, low HDL levels, high LDL levels,hyperlipidemia, hypertriglyceridemia or dyslipidemia; lipoproteinaberrations; decreased triglycerides; inflammation (e.g., liverinflammation and/or inflammation of adipose tissue), fatty liverdisease; non-alcoholic fatty liver disease; hyperglycemia; impairedglucose tolerance (IGT); hyperinsulinemia; high cholesterol (e.g., highLDL levels and hypercholesterolemia); cardiovascular disease such as,heart disease including coronary heart disease, congestive heartfailure, stroke, peripheral vascular disease, atherosclerosis;arteriosclerosis, and hypertension; Syndrome X; vascular restenosis;neuropathy; retinopathy; neurodegenerative disease; endothelialdysfunction, respiratory dysfunction, renal disease (e.g., nephropathy);pancreatitis; polycystic ovarian syndrome; elevated uric acid levels;haemochromatosis (iron overload); acanthosis nigricans (dark patches onthe skin); and cancer (e.g., myeloma (multiple myeloma, plasmacytoma,localized myeloma, or extramedullary myeloma), or an ovarian (e.g.,epithelial ovarian), breast, colon, endometrial, liver, kidney,pancreatic, gastric, uterine, or colon cancer); and otherdisorders/conditions associated with one or more of the above diseasesor conditions, or with overweight (e.g., BMI of 25 kg/m²), or with toomuch body fat.

As used herein, “in combination with” or “combination therapies” refersto any form of administration such that additional therapies (e.g.,second, third, fourth, etc.) are still effective in the body (e.g.,multiple compounds are simultaneously effective in the subject, whichmay include synergistic effects of those compounds). Effectiveness maynot correlate to measurable concentration of the agent in blood, serum,or plasma. For example, the different therapeutic compounds can beadministered either in the same formulation or in separate formulations,either concomitantly or sequentially, and on different schedules. Thus,a subject that receives such treatment can benefit from a combinedeffect of different therapies. One or more ALK7-binding proteinsprovided herein can be administered concurrently with, prior to, orsubsequent to, one or more other additional agents and/or supportivetherapies. In general, each therapeutic agent will be administered at adose and/or on a time schedule determined for that particular agent. Theparticular combination to employ in a regimen will take into accountcompatibility of the antagonist of the present disclosure with therapyand/or the desired outcome.

The methods and techniques of the present disclosure are generallyperformed according to known conventional methods and as described invarious general and more specific references that are cited anddiscussed throughout the present disclosure unless otherwise indicated.See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 3rded., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.(2001) and Ausubel et al., Current Protocols in Molecular Biology,Greene Publishing Associates (1992), and Harlow and Lane Antibodies: ALaboratory Manual Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y. (1990), all of which are herein incorporated by reference.

The terms “cancer,” “tumor,” “cancerous,” and “malignant” refer to ordescribe the physiological condition in mammals that is typicallycharacterized by unregulated cell growth. Examples of cancers includebut are not limited to, carcinoma including adenocarcinomas, lymphomas,blastomas, melanomas, sarcomas, and leukemias. More particular examplesof such cancers include squamous cell cancer, small-cell lung cancer,non-small cell lung cancer, gastrointestinal cancer, Hodgkin's andnon-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma,cervical cancer, ovarian cancer, liver cancer such as hepatic carcinomaand hepatoma, bladder cancer, breast cancer (including hormonallymediated breast cancer, see, e.g., Innes et al., Br. J. Cancer94:1057-1065 (2006)), colon cancer, colorectal cancer, endometrialcarcinoma, myeloma (such as multiple myeloma), salivary gland carcinoma,kidney cancer such as renal cell carcinoma and Wilms' tumors, basal cellcarcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer,testicular cancer, esophageal cancer, various types of head and neckcancer and cancers of mucinous origins, such as, mucinous ovariancancer, cholangiocarcinoma (liver) and renal papillary carcinoma. In aparticular embodiment, the cancer is breast, endometrial, or uterinecancer. In another embodiment, the cancer is a myeloma (e.g., multiplemyeloma, plasmacytoma, localized myeloma, and extramedullary myeloma),or endometrial, gastric, liver, colon, renal or pancreatic cancer.

The terms “polynucleotide” and “nucleic acid” are used interchangeablyand are intended to encompass a singular nucleic acid as well as pluralnucleic acids, and refers to an isolated nucleic acid molecule orconstruct, e.g., messenger RNA (mRNA), complementary DNA (cDNA), orplasmid DNA (pDNA). In certain embodiments, a polynucleotide comprises aconventional phosphodiester bond or a non-conventional bond (e.g., anamide bond, such as found in peptide nucleic acids (PNA)). The term“nucleic acid” refers to any one or more nucleic acid segments, e.g.,DNA, cDNA, or RNA fragments, present in a polynucleotide. When appliedto a nucleic acid or polynucleotide, the term “isolated” refers to anucleic acid molecule, DNA or RNA, which has been removed from itsnative environment, for example, a recombinant polynucleotide encodingan antigen binding protein contained in a vector is considered isolatedfor the purposes of the present disclosure. Further examples of anisolated polynucleotide include recombinant polynucleotides maintainedin heterologous host cells or purified (partially or substantially) fromother polynucleotides in a solution. Isolated RNA molecules include invivo or in vitro RNA transcripts of polynucleotides of the presentdisclosure. Isolated polynucleotides or nucleic acids according to thepresent disclosure further include such molecules producedsynthetically. In addition, polynucleotides or nucleic acids can includeregulatory elements such as promoters, enhancers, ribosome bindingsites, or transcription termination signals.

The term “vector” means a construct, which is capable of delivering, andin some embodiments expressing, one or more gene(s) or sequence(s) ofinterest in a host cell. Examples of vectors include, but are notlimited to, viral vectors, naked DNA or RNA expression vectors, plasmid,cosmid or phage vectors, DNA or RNA expression vectors associated withcationic condensing agents, DNA or RNA expression vectors encapsulatedin liposomes, and certain eukaryotic cells, such as producer cells.

The term “host cell” refers to a cell or a population of cells harboringor capable of harboring a recombinant nucleic acid. Host cells can beprokaryotic (e.g., E. coli), or eukaryotic. The host cells can be fungalcells including yeast such as Saccharomyces cerevisiae, Pichia pastoris,or Schizosaccharomyces pombe. The host cells also be any of variousanimal cells, such as insect cells (e.g., Sf-9) or mammalian cells(e.g., HEK293F, CHO, COS-7, NIH-3T3, NS0, PER.C6®, and hybridoma). Infurther embodiments, the host cells is a CHO cell selected from thegroup consisting of CHO-K, CHO-0 CHO-Lec10, CHO-Lec13, CHO-Lec1, CHOPro⁻5, and CHO dhfr⁻. In particular embodiments, the host cell is ahybridoma.

The terms “polypeptide,” “peptide,” and “protein” are usedinterchangeably herein to refer to polymers of amino acids of anylength. The polymer can be linear or branched, it can comprise modifiedamino acids, and it can be interrupted by non-amino acids. The termsalso encompass an amino acid polymer that has been modified naturally orby intervention; for example, disulfide bond formation, glycosylation,lipidation, acetylation, phosphorylation, or any other manipulation ormodification, such as conjugation with a labeling component. Alsoincluded within the definition are, for example, polypeptides containingone or more analogs of an amino acid (including, for example, unnaturalamino acids, etc.), as well as other modifications known in the art. Itis understood that, because in some embodiments the providedALK7-binding proteins are based upon antibodies, the ALK7-bindingproteins can occur as single chains or associated chains.

A “recombinant” polypeptide, protein or antibody refers to polypeptide,protein or antibody produced via recombinant DNA technology.Recombinantly produced polypeptides, proteins and antibodies expressedin host cells are considered isolated for the purpose of the presentdisclosure, as are native or recombinant polypeptides which have beenseparated, fractionated, or partially or substantially purified by anysuitable technique.

Also included in the present disclosure are fragments, variants, orderivatives of polypeptides, and any combination thereof. The term“fragment” when referring to polypeptides and proteins include anypolypeptides or proteins which retain at least some of the properties ofthe reference polypeptide or protein. Fragments of polypeptides includeproteolytic fragments, as well as deletion fragments.

The term “variant” refers to an antibody or polypeptide sequence thatdiffers from that of a parent antibody or polypeptide sequence by virtueof at least one amino acid modification. Variants of antibodies orpolypeptides include fragments, and also antibodies or polypeptides withaltered amino acid sequences due to amino acid substitutions, deletions,or insertions. Variants can be naturally or non-naturally occurring.Non-naturally occurring variants can be produced using art-knownmutagenesis techniques. Variant polypeptides can comprise conservativeor non-conservative amino acid substitutions, deletions or additions.

The term “derivatives” as applied to antibodies or polypeptides refersto antibodies or polypeptides which have been altered so as to exhibitadditional features not found on the native antibody or polypeptide. Anexample of a “derivative” antibody is a fusion or a conjugate with asecond polypeptide or another molecule (e.g., a polymer such as PEG, achromophore, or a fluorophore) or atom (e.g., a radioisotope).

The term “amino acid substitution” refers to replacing an amino acidresidue present in a parent sequence with another amino acid residue. Anamino acid can be substituted in a parent sequence, for example, viachemical peptide synthesis or through known recombinant methods.Accordingly, references to a “substitution at position X” or“substitution at position X” refer to the substitution of an amino acidresidue present at position X with an alternative amino acid residue. Insome embodiments, substitution patterns can described according to theschema AXY, wherein A is the single letter code corresponding to theamino acid residue naturally present at position X, and Y is thesubstituting amino acid residue. In other embodiments, substitutionpatterns can described according to the schema XY, wherein Y is thesingle letter code corresponding to the amino acid residue substitutingthe amino acid residue naturally present at position X.

A “conservative amino acid substitution” is one in which the amino acidresidue is replaced with an amino acid residue having a similar sidechain. Families of amino acid residues having similar side chains havebeen previously defined, including basic side chains (e.g., Lys, Arg,His), acidic side chains (e.g., Asp, Glu), uncharged polar side chains(e.g., Gly, Asp, Gln, Ser, Thr, Tyr, Cys), nonpolar side chains (e.g.,Ala, Val, Leu, lie, Pro, Phe, Met, Trp), beta-branched side chains(e.g., Thr, Val, Ile) and aromatic side chains (e.g., Tyr, Phe, Trp,His). Thus, if an amino acid residue in a polypeptide is replaced withanother amino acid residue from the same side chain family, thesubstitution is considered to be conservative. In another embodiment, astring of amino acid residues can be conservatively replaced with astructurally similar string that differs in order and/or composition ofside chain family members.

Non-conservative substitutions include those in which (a) a residuehaving an electropositive side chain (e.g., Arg, His, or Lys) issubstituted for, or by, an electronegative residue (e.g., Glu or Asp),(b) a hydrophilic residue (e.g., Ser or Thr) is substituted for, or by,a hydrophobic residue (e.g., Ala, Leu, lie, Phe, or Val), (c) a Cys orPro is substituted for, or by, any other residue, or (d) a residuehaving a bulky hydrophobic or aromatic side chain (e.g., Val, His, lie,or Trp) is substituted for, or by, one having a smaller side chain(e.g., Ala or Ser) or no side chain (e.g., Gly).

Other substitutions can be readily identified. For example, for theamino acid alanine, a substitution can be taken from any one of D-Ala,Gly, beta-Ala, L-Cys and D-Cys. For lysine, a replacement can be any oneof D-Lys, Arg, D-Arg, homo-Arg, Met, D-Met, ornithine, or D-omithine.Generally, substitutions in functionally important regions that can beexpected to induce changes in the properties of isolated polypeptidesare those in which (a) a polar residue (e.g., Ser or Thr) is substitutedfor (or by) a hydrophobic residue (e.g., Leu, Ile, Phe, or Ala); (b) aCys residue is substituted for (or by) any other residue; (c) a residuehaving an electropositive side chain (e.g., Lys, Arg, or His), issubstituted for (or by) a residue having an electronegative side chain(e.g., Glu or Asp); or (d) a residue having a bulky side chain (e.g.,Phe) is substituted for (or by) one not having such a side chain (e.g.,Gly). The likelihood that one of the foregoing non-conservativesubstitutions can alter functional properties of the protein is alsocorrelated to the position of the substitution with respect tofunctionally important regions of the protein: some non-conservativesubstitutions can accordingly have little or no effect on biologicalproperties.

The term “amino acid insertion” refers to introducing a new amino acidresidue between two amino acid residues present in the parent sequence.An amino acid residue can be inserted in a parent sequence, for example,via chemical peptide synthesis or through recombinant methods known inthe art. Accordingly, the phrases “insertion between positions X and Y”or “insertion between Kabat positions X and Y,” wherein X and Ycorrespond to amino acid residue positions (e.g., a cysteine amino acidresidue insertion between positions 239 and 240), refers to theinsertion of an amino acid residue between the X and Y positions, andalso to the insertion in a nucleic acid sequence of a codon encoding anamino acid residue between the codons encoding the amino acid residuesat positions X and Y.

The term “percent sequence identity” or “percent identity” between twopolynucleotide or polypeptide sequences refers to the number ofidentical matched positions shared by the sequences over a comparisonwindow, taking into account additions or deletions (i.e., gaps) thatmust be introduced for optimal alignment of the two sequences. A matchedposition is any position where an identical nucleotide or amino acid ispresented in both the target and reference sequence. Gaps presented inthe target sequence are not counted since gaps are not nucleotides oramino acids. Likewise, gaps presented in the reference sequence are notcounted since target sequence nucleotides or amino acids are counted,not nucleotides or amino acids from the reference sequence. Thepercentage of sequence identity is calculated by determining the numberof positions at which the identical amino-acid residue or nucleic acidbase occurs in both sequences to yield the number of matched positions,dividing the number of matched positions by the total number ofpositions in the window of comparison and multiplying the result by 100to yield the percentage of sequence identity. The comparison ofsequences and determination of percent sequence identity between twosequences can be accomplished using readily available software programs.Suitable software programs are available from various sources, and foralignment of both protein and nucleotide sequences. One suitable programto determine percent sequence identity is bl2seq, part of the BLASTsuite of program available from the U.S. government's National Centerfor Biotechnology Information BLAST web site (blast.ncbi.nlm.nih.gov).Bl2seq performs a comparison between two sequences using either theBLASTN or BLASTP algorithm. BLASTN is used to compare nucleic acidsequences, while BLASTP is used to compare amino acid sequences. Othersuitable programs are, e.g., Needle, Stretcher, Water, or Matcher, partof the EMBOSS suite of bioinformatics programs and also available fromthe European Bioinformatics Institute (EBI) at www.ebi.ac.uk/Tools/psa.

The structure for carrying a CDR or a set of CDRs will generally be ofan antibody heavy or light chain sequence or substantial portion thereofin which the CDR or set of CDRs is located at a location correspondingto the CDR or set of CDRs of naturally occurring VH and VL antibodyvariable domains encoded by rearranged immunoglobulin genes. Thestructures and locations of immunoglobulin variable domains and theirCDRs can readily be determined by one skilled in the art using programsand known variable domain residue numbering systems such as Chothia,Chothia+, and Kabat can routinely be determined by reference to Kabat(Kabat et al., Sequences of Proteins of Immunological Interest. 4thEdition. U.S. DHHS. 1987, and tools available on the Internet (e.g., atbioinf.org.uk/abysis/sequence_input/key_annotation/key_annotation. html;and immuno.bme.nwu.edu)), herein incorporated by reference in itsentirety.

CDRs can also be carried by other scaffolds such as fibronectin,cytochrome B, albumin (e.g., ALBUdAb (Domantis/GSK) and ALB-Kunitz(Dyax)), unstructured repeat sequences of 3 or 6 amino acids (e.g.,PASylation® technology and XTEN® technology), and sequences containingelastin-like repeat domains (see, e.g., U.S. Pat. Appl. No. 61/442,106,which is herein incorporated by reference in its entirety).

A CDR amino acid sequence substantially as set out herein can be carriedas a CDR in a human variable domain or a substantial portion thereof.The HCDR3 sequences substantially as set out herein representembodiments of the present disclosure and each of these may be carriedas a HCDR3 in a human heavy chain variable domain or a substantialportion thereof.

Variable domains employed in the present disclosure can be obtained fromany germ-line or rearranged human variable domain, or can be a syntheticvariable domain based on consensus sequences of known human variabledomains. A CDR sequence (e.g., CDR3) can be introduced into a repertoireof variable domains lacking a CDR (e.g., CDR3), using recombinant DNAtechnology.

For example, Marks et al., (Bio/Technology 10:779-783 (1992); which isherein incorporated by reference in its entirety) provide methods ofproducing repertoires of antibody variable domains in which consensusprimers directed at or adjacent to the 5′ end of the variable domainarea are used in conjunction with consensus primers to the thirdframework region of human VH genes to provide a repertoire of VHvariable domains lacking a CDR3. Marks et al., further describe how thisrepertoire can be combined with a CDR3 of a particular antibody. Usinganalogous techniques, the CDR3-derived sequences of the presentdisclosure can be shuffled with repertoires of VH or VL domains lackinga CDR3, and the shuffled complete VH or VL domains combined with acognate VL or VH domain to provide antigen binding proteins. Therepertoire can then be displayed in a suitable host system such as thephage display system of Intl. Appl. Publ. No. WO92/01047 or any of asubsequent large body of literature, including Kay et al., (1996) PhageDisplay of Peptides and Proteins: A Laboratory Manual, San Diego:Academic Press, so that suitable antigen binding proteins may beselected. A repertoire can consist of from anything from 104 individualmembers upwards, for example from 10⁶ to 10⁸, or 10¹⁰, members. Othersuitable host systems include yeast display, bacterial display, T7display, and ribosome display. For a review of ribosome display for seeLowe et al., Curr. Pharm. Biotech. 517-527 (2004) and Intl. Appl. Publ.No. WO92/01047, each of which is herein incorporated by reference hereinin its entirety. Analogous shuffling or combinatorial techniques arealso disclosed by Stemmer (Nature 370:389-391 (1994), which is hereinincorporated by reference in its entirety), which describes thetechnique in relation to a β-lactamase gene but observes that theapproach may be used for the generation of antibodies.

An ALK7-binding protein (e.g., an anti-ALK7 antibody) is said to“compete” with a reference molecule for binding to ALK7 if it binds toALK7 to the extent that it blocks, to some degree, binding of thereference molecule to ALK7. The ability of proteins to compete forbinding to ALK7 and thus to interfere with, block or “cross-block” oneanother's binding to ALK7 can be determined by any standard competitivebinding assay known in the art including, for example, a competitionELISA assay, surface plasmon resonance (SPR; BIACORE®, Biosensor,Piscataway, N.J.) or according to methods described by Scatchard et al.(Ann. N.Y Acad. Sci. 51:660-672 (1949)). An ALK7-binding protein may besaid to competitively inhibit binding of the reference molecule to ALK7,for example, by at least 90%, at least 80%, at least 70%, at least 60%,or at least 50%. According to some embodiments, the ALK7-binding proteincompetitively inhibits binding of the reference molecule to ALK7, by atleast 90%, at least 80%, at least 70%, at least 60%, or at least 50%/c.According to other embodiments, the ALK7-binding protein competitivelyinhibits binding of a reference molecule to ALK7, by at least 90%, atleast 80%, at least 70%, at least 60%, or at least 50%.

ALK7-Binding Proteins

Proteins that specifically bind ALK7 are provided. In some embodiments,antagonist ALK-7 binding proteins are provided. In some embodiments, theALK7 binding proteins are antibodies. In further embodiments, theantibodies are antagonist anti-ALK7 antibodies.

As used herein, the term “ALK7” refers to a family of activinreceptor-like kinase-7 proteins from any species and variants derivedfrom such ALK7 proteins by mutagenesis or other modification. Referenceto ALK7 herein is understood to be a reference to any one of thecurrently identified forms. Members of the ALK7 family are generallytransmembrane proteins, composed of a ligand-binding extracellulardomain with a cysteine-rich region, a transmembrane domain, and acytoplasmic domain with predicted serine/threonine kinase activity.There are various naturally occurring isoforms of human ALK7. Thesequence of canonical human ALK7 isoform 1 precursor protein (NCBI RefSeq NP_660302.2) is as follows:

(SEQ ID NO: 85)   1 MTRALCSALR QALLLLAAAA ELSPGLKCVC LLCDSSNFTC    QTEGACWASV MLTNGKEQVI 61 KSCVSLPELN AQVFCHSSNN VTKTECCFTD FCNNITLHLP    TASPNAPKLG PMELAIIITV121 PVCLLSIAAM LTVWACQGRQ CSYRKKKRPN VEEPLSECNL    VNAGKTLKDL IYDVTASGSG181 SGLPLLVQRT IARTIVLQEI VGKGRFGEVW HGRWCGEDVA    VKIFSSRDER SWFREAEIYQ241 TVMLRHENIL GFIAADNKDN GTWTQLWLVS EYHEQGSLYD    YLNRNIVTVA GMIKLALSIA301 SGLAHLHMEI VGTQGKPAIA HRDIKSKNIL VKKCETCAIA    DLGLAVKHDS ILNTIDIPQN361 PKVGTKRYMA PEMLDDTMNV NIFESFKRAD IYSVGLVYWE    IARRCSVGGI VEEYQLPYYD421 MVPSDPSIEE MRKVVCDQKF RPSIPNQWQS CEALRVMGRI    MRECWYANGA ARLTALRIKK 481 TISQLCVKED CKAThe signal peptide is indicated by a single underline and theextracellular domain is indicated in bold font.

In some embodiments, the ALK7-binding protein binds ALK7 with anaffinity that is at least, 100, 500, or 1000 times greater than theaffinity of the ALK7-binding protein for a control protein that is not aTGF-beta receptor family member. In certain embodiments, theALK7-binding protein binds ALK7 and has a dissociation constant (K_(D))of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <10 pM, <1 pM, or <0.1 pM. Insome embodiments, the ALK7-binding protein has a K_(D) for human ALK7within the range of ≤1 μM and ≥0.1 pM, ≤100 μM and ≤0.1 pM, or ≤100 μMand ≤1 pM.

In some embodiments, BIACORE® analysis is used to determine the abilityof an ALK7-binding protein (e.g., an anti-ALK7 antibody) to competewith/block the binding to ALK7 protein by a reference ALK7-bindingprotein (e.g., an anti-ALK7 antibody). In a further embodiment in whicha BIACORE® instrument (for example the BIACORE® 3000) is operatedaccording to the manufacturer's recommendations, ALK7-Fc fusion proteinis captured on a CM5 BIACORE® chip by previously attached anti-niFc IgGto generate an ALK7-coated surface. Typically 200-800 resonance units ofALK7-Fc (dimeric) would be coupled to the chip (an amount that giveseasily measurable levels of binding but that is readily saturable by theconcentrations of test reagent being used).

The two ALK7-binding proteins (termed A* and B*) to be assessed fortheir ability to compete with/block each other are mixed at a one to onemolar ratio of binding sites in a suitable buffer to create a testmixture. When calculating the concentrations on a binding site basis themolecular weight of an ALK7-binding protein is assumed to be the totalmolecular weight of the ALK7-binding protein divided by the number ofALK7-binding sites on that ALK7-binding protein. The concentration ofeach ALK7-binding protein (i.e., A* and B*) in the test mixture shouldbe high enough to readily saturate the binding sites for thatALK7-binding protein on the ALK7-Fc molecules captured on the BIACORE®chip. The A* and B* ALK7-binding proteins in the mixture are at the samemolar concentration (on a binding basis) and that concentration wouldtypically be between 1.00 and 1.5 micromolar (on a binding site basis).Separate solutions containing ALK7-binding protein A* alone andALK7-binding protein B* alone are also prepared. ALK7-binding protein A*and ALK7-binding protein B* in these solutions should be in the samebuffer and at the same concentration as in the test mixture. The testmixture is passed over the ALK7-Fc-coated BIACORE® chip and the totalamount of binding recorded. The chip is then treated in such a way as toremove the bound ALK7-binding proteins without damaging the chip-boundALK7-Fc. Typically, this is done by treating the chip with 30 mM HCl for60 seconds. The solution of ALK7-binding protein A* alone is then passedover the ALK7-Fc-coated surface and the amount of binding recorded. Thechip is again treated to remove the bound antibody without damaging thechip-bound ALK7-Fc. The solution of ALK7-binding protein B* alone isthen passed over the ALK7-Fc-coated surface and the amount of bindingrecorded. The maximum theoretical binding of the mixture of ALK7-bindingprotein A* and ALK7-binding protein B* is next calculated, and is thesum of the binding of each ALK7-binding protein when passed over theALK7 surface alone. If the actual recorded binding of the mixture isless than this theoretical maximum then the two ALK7-binding proteinsare competing with/blocking each other. Thus, in general, a blockingALK7-binding protein is one which will bind to ALK7 in the aboveBIACORE® blocking assay such that during the assay and in the presenceof a second ALK7-binding protein the recorded binding is between 80% and0.1% (e.g., 80%>to 4%) of the maximum theoretical binding, specificallybetween 75% and 0.1% (e.g., 75% to 4%) of the maximum theoreticalbinding, and more specifically between 70% and 0.1% (e.g., 70% to 4%) ofmaximum theoretical binding (as defined above) of the two ALK7-bindingproteins in combination.

The BIACORE® assay described above is an exemplary assay used todetermine if two ALK7-binding proteins such as anti-ALK7 antibodiescompete with/block each other for binding ALK7. On rare occasions,particular ALK7-binding proteins may not bind to ALK7-Fc coupled viaanti-Fc IgG to a CM5 BIACORE® chip (this might occur when the relevantbinding site on ALK7 is masked or destroyed by ALK7 linkage to Fc). Insuch cases, blocking can be determined using a tagged version of ALK7,for example C-terminal His-tagged ALK7. In this particular format, ananti-His antibody would be coupled to the BIACORE® chip and then theHis-tagged ALK7 would be passed over the surface of the chip andcaptured by the anti-His antibody. The cross-blocking analysis would becarried out essentially as described above, except that after each chipregeneration cycle, new His-tagged ALK7 would be loaded back onto thesurface coated with anti-His antibody. Moreover, various other knowntags and tag binding protein combinations can be used for such ablocking analysis (e.g., HA tag with anti-HA antibodies; FLAG tag withanti-FLAG antibodies; biotin tag with streptavidin). The followinggenerally describes an ELISA assay for determining whether anALK7-binding protein blocks or is capable of blocking the binding of areference ALK7-binding protein to ALK7.

In some embodiments, an ELISA is used to determine the ability of anALK7-binding protein (e.g., an anti-ALK7 antibody) to compete forbinding to ALK7 with a reference ALK7-binding protein (e.g., ananti-ALK7 antibody or ALK7 ligand). The general principle of such anassay is to have a reference ALK7-binding protein (e.g., an anti-ALK7antibody) coated onto the wells of an ELISA plate. An excess amount of asecond potentially blocking, test ALK7-binding protein is added insolution (i.e., not bound to the ELISA plate). A limited amount of ALK7(or alternatively ALK7-Fc) is then added to the wells. The coatedreference ALK7-binding protein and the test ALK7-binding protein insolution compete for binding of the limited number of ALK7 (or ALK7-Fc)molecules. The plate is washed to remove ALK7 that has not been bound bythe coated reference ALK7-binding protein and to also remove the test,solution-phase ALK7-binding protein as well as any complexes formedbetween the test, solution-phase ALK7-binding protein and ALK7. Theamount of bound ALK7 is then measured using an appropriate ALK7detection reagent. A test ALK7-binding protein in solution that is ableto block binding of the coated reference ALK7-binding protein to ALK7will be able to cause a decrease in the number of ALK7 molecules thatthe coated reference ALK7-binding protein can bind relative to thenumber of ALK7 molecules that the coated reference ALK7-binding proteincan bind in the absence of the second, solution-phase test ALK7-bindingprotein. The background signal for the assay is defined as the signalobtained in wells with the coated reference ALK7-binding protein,solution-phase test ALK7-binding protein, ALK7 buffer only (i.e., noALK7) and ALK7 detection reagents. The positive control signal for theassay is defined as the signal obtained in wells with the coatedreference ALK7-binding protein, solution-phase test ALK7-binding proteinbuffer only (i.e., no solution-phase test ALK7-binding protein), ALK7and an ActRII receptor (e.g., ActRIIA or ActRIIB) detection reagents.The ELISA assay is be run in such a manner so as to have the positivecontrol signal at least 3 times the background signal. As a control formethodologic artifacts, the cross-blocking assay may be run in theformat just described and also reversed, with the test ALK7-bindingprotein as the coated antibody and the reference ALK7-binding protein asthe solution-phase antibody.

In some embodiments, the ALK7-binding protein binds ALK7 with anaffinity that is at least, 100, 500, or 1000 times greater than theaffinity of the ALK7-binding protein for a control protein that is not aTGF-beta receptor family member. In additional embodiments, theALK7-binding protein binds ALK7 with an affinity that is at least, 100,500, or 1000 times greater than the affinity of the ALK7-binding proteinfor a control protein that is not a TGF-beta receptor family member. Incertain embodiments, the ALK7-binding protein binds ALK7 and has adissociation constant (K_(D)) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM,<10 pM, <1 pM, or <0.1 pM. In some embodiments, the ALK7-binding proteinhas a K_(D) for human ALK7 within the range of ≤1 μM and ≥0.1 pM, ≤100μM and ≥0.1 pM, or ≤100 μM and ≥1 pM.

In some embodiments, a cell-based lipolysis inhibition assay is used todetermine the ability of an ALK7-binding protein (e.g., an antagonistanti-ALK7 antibody) to reduce (inhibit) ALK7-mediated inhibition oflipolysis in mammalian white adipocytes. In some embodiments, thelipolysis inhibition assay is performed using mature whit adipocytes(e.g., human, mouse, or rat) to determine the ability of an ALK7-bindingprotein (e.g., an anti-ALK7 antibody) to reduce ALK7 activity. Kits,reagents and methods for conducting a lipolysis assay are commerciallyavailable and known in the art. In particular embodiments, the lipolysisinhibition assay is performed as provided in the Examples herein. Inother embodiments, the assay is performed according to the instructionsand reagents as provided in a commercially available lipolysis assay kit(e.g., BioAssay Systems, EnzyChrom™ Adipolysis Assay Kit, Cat. No.EAPL-200; Abeam Cat. No. ab185433; Zen-Bio, Cat. No. LIP-1-NCL;BioVision, Cat. No. K577-100; Sigma-Aldrich, Cat. No. MAK211; andAdipoLyze™ Lipolysis Detection Assay, Lonza, Cat. No. 193339).

In some embodiments, the ALK7-binding protein, an ALK7-binding proteinis an ALK7 antagonist and increases lipolysis by 5% to 100%, 10% to 80%,or 10%0/to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in adipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%.In some embodiments, the ALK7-binding protein increase lipolysis in amature white adipose cell by 5% to 100%, 10% 95%, 10 to 90%, 10 to 85%,10 to 80%, 10 to 75%, 10 to 70%, 10 to 65%, 10 to 60%, 10 to 55%, 10 to50%, or 10 to 45%, as determined using standard techniques andconditions in a lipolysis inhibition assay performed in the presence ofactivin B (50 ng/ml) (e.g., as described in the examples herein). Inanother embodiment, an ALK7-binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a mature white adipose cell by at least 5%, 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, or 95%, or by about 100%, as determined,using standard techniques and conditions in a lipolysis inhibition assayperformed in the presence of activin B (50 ng/ml) (e.g., as described inthe examples herein).

Pharmacodynamic parameters dependent on ALK7 signaling can be measuredas endpoints for in vivo testing of ALK7-binding proteins in order toidentify those binding proteins that are able to neutralize ALK7 andprovide a therapeutic benefit. An ALK7 neutralizing binding agent isdefined as one capable of causing a statistically significant change, ascompared to vehicle-treated animals, in such a pharmacodynamicparameter. Such in vivo testing can be performed in any suitable mammal(e.g., mouse, rat, or monkey).

In some embodiments, an ALK7-binding protein is an antibody thatspecifically binds ALK7. In additional embodiments, the ALK7-bindingprotein is a full-length anti-ALK7 antibody. In additional embodiments,the antibody is a monoclonal antibody, a recombinant antibody, a humanantibody, a humanized antibody, a chimeric antibody, a bi-specificantibody, a multi-specific antibody, or an ALK7-binding antibodyfragment thereof.

In some embodiments, the anti-ALK7 antibody is an ALK7-binding antibodyfragment. In some embodiments, the ALK7-binding antibody fragment is a:Fab, Fab′, F(ab′)₂, Fv fragment, diabody, or single chain antibodymolecule. In additional embodiments, the ALK7-antibody is a Fd, singlechain Fv(scFv), disulfide linked Fv, V-NAR domain, IgNar, intrabody,IgGΔCH2, minibody, F(ab′)₃, tetrabody, triabody, diabody, single-domainantibody, DVD-Ig, Fcab, mAb², (scFv)₂, scFv-Fc or bis-scFv.

In additional embodiments the ALK7-binding protein is an antibody thatincludes a VH and a VL. In some embodiments the anti-ALK7 antibodyfurther includes a heavy chain constant region or fragment thereof. Insome embodiments, the antibody comprises a heavy chain immunoglobulinconstant region selected from the group consisting of: (a) a human IgAconstant region, or fragment thereof; (b) a human IgD constant region,or fragment thereof; (c) a human IgE constant domain, or fragmentthereof; (d) a human IgG1 constant region, or fragment thereof; (e) ahuman IgG2 constant region, or fragment thereof; (f) a human IgG3constant region, or fragment thereof; (g) a human IgG4 constant region,or fragment thereof; and (h) a human IgM constant region, or fragmentthereof. In certain embodiments an ALK7-binding protein comprises aheavy chain constant region or fragment thereof, e.g., a human IgGconstant region or fragment thereof. In further embodiments, theALK7-binding protein comprises a heavy chain immunoglobulin constantdomain that has, or has been mutated to have altered effector functionand/or half-life.

In particular embodiments, the ALK7-binding protein is an antibody thatcomprises an IgG1 heavy chain constant region containing a mutation thatdecreases effector function (see, e.g., Idusogie et al., J. Immunol.166:2571-2575 (2001); Sazinsky et al., PNAS USA 105:20167-20172 (2008);Davis et al., J. Rheumatol. 34:2204-2210 (2007); Bolt et al., Eur. J.Immunol. 23:403-411 (1993); Alegre et al., Transplantation 57:1537-1543(1994); Xu et al., Cell Immunol. 200:16-26 (2000); Cole et al.,Transplantation 68:563-571 (1999); Hutchins et al., PNAS USA92:11980-11984 (1995); Reddy et al., J. Immunol. 164:1925-1933 (2000);WO97/11971, and WO07/106585; U.S. Appl. Publ. 2007/0148167A1; McEarchernet al., Blood 109:1185-1192 (2007); Strohl, Curr. Op. Biotechnol.20:685-691 (2009); and Kumagai et al., J. Clin. Pharmacol. 47:1489-1497(2007), each of which is herein incorporated by reference in itsentirety).

In some embodiments, the heavy chain constant region or fragment thereofincludes one or more amino acid substitutions relative to a wild-typeIgG constant domain wherein the modified IgG has decreased ADCC comparedto the half-life of an IgG having the wild-type IgG constant domain.Examples of Fc sequence engineering modifications contained in theprovided antibodies that decrease ADCC include one or more modificationscorresponding to: IgG1-K326W, E333S; IgG2-E333S; IgG1-N297A; IgG1-L234A,L235A; IgG2-V234A, G237A; IgG4-L235A, G237A, E318A; IgG4-S228P, L236E;IgG2-EU sequence 118-260; IgG4-EU sequence 261-447; IgG2-H268Q, V309L,A330S, A331S; IgG1-C220S, C226S, C229S, P238S; IgG1-C226S, C229S, E233P,L234V, L235A; and IgG1-L234F, L235E, P331S, wherein the positionnumbering is according to the EU index as in Kabat.

In certain embodiments an ALK7-binding protein comprises a heavy chainimmunoglobulin constant domain that has, or has been mutated to have,reduced CDC activity. In particular embodiments, the ALK7-bindingprotein is an antibody that comprises an IgG1 heavy chain constantregion containing a mutation that decreases CDC activity (see, e.g.,WO97/11971 and WO07/106585; U.S. Appl. Publ. 2007/0148167A1; McEarchernet al., Blood 109:1185-1192 (2007); Hayden-Ledbetter et al., Clin.Cancer 15:2739-2746 (2009); Lazar et al., PNAS USA 103:4005-4010 (2006);Bruckheimer et al., Neoplasia 11:509-517 (2009); Strohl, Curr. Op.Biotechnol. 20:685-691 (2009); and Sazinsky et al., PNAS USA105:20167-20172 (2008); each of which is herein incorporated byreference in its entirety). Examples of Fc sequence engineeringmodifications contained in an anti-ALK7 antibody that decrease CDCinclude one or more modifications corresponding to: IgG1-S239D. A330L,1332E; IgG2 EU sequence 118-260; IgG4-EU sequence 261-447; IgG2-H268Q,V309L, A330S, A331S; IgG1-C226S, C229S, E233P, L234V, L235A; IgG1-L234F,L235E, P331S; and IgG1-C226S, P230S.

In further embodiments, the heavy chain constant region or fragmentthereof includes one or more amino acid substitutions relative to awild-type IgG constant domain wherein the modified IgG has an increasedhalf-life compared to the half-life of an IgG having the wild-type IgGconstant domain. For example, the IgG constant domain can contain one ormore amino acid substitutions of amino acid residues at positions251-257, 285-290, 308-314, 385-389, and 428-436, wherein the amino acidposition numbering is according to the EU index as set forth in Kabat.In certain embodiments the IgG constant domain can contain one or moreof a substitution of the amino acid at Kabat position 252 with Tyr, Phe,Trp, or Thr; a substitution of the amino acid at Kabat position 254 withThr; a substitution of the amino acid at Kabat position 256 with Ser,Arg, Gln, Glu, Asp, or Thr; a substitution of the amino acid at Kabatposition 257 with Leu; a substitution of the amino acid at Kabatposition 309 with Pro; a substitution of the amino acid at Kabatposition 311 with Ser; a substitution of the amino acid at Kabatposition 428 with Thr, Leu, Phe, or Ser; a substitution of the aminoacid at Kabat position 433 with Arg, Ser, Iso, Pro, or Gln; or asubstitution of the amino acid at Kabat position 434 with Trp, Met, Ser,His, Phe, or Tyr. More specifically, the IgG constant domain can containamino acid substitutions relative to a wild-type human IgG constantdomain including a substitution of the amino acid at Kabat position 252with Tyr, a substitution of the amino acid at Kabat position 254 withThr, and a substitution of the amino acid at Kabat position 256 withGlu.

In additional embodiments, the ALK7-binding protein is an antibody thatcomprises a light chain immunoglobulin constant region. In a furtherembodiment, the antibody comprises a human Ig kappa constant region or ahuman Ig lambda constant region.

In some embodiments, the ALK7-binding protein comprises a set of CDRs:VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein theCDRs are present in a VH and a VL pair disclosed in Table 1A. In furtherembodiments, the ALK7-binding protein comprises a set of CDRs whereinthe CDRs are present in a VH and a VL pair selected from the groupconsisting of: (a) a VH sequence of SEQ ID NO:4, and a VL sequence ofSEQ ID NO:13; (b) a VH sequence of SEQ ID NO:22, and a VL sequence ofSEQ ID NO:31; (c) a VH sequence of SEQ ID NO:40, and a VL sequence ofSEQ ID NO:49; and (d) a VH sequence of SEQ ID NO:58 and a VL sequence ofSEQ ID NO:67; and wherein the protein binds ALK7.

In some embodiments, the ALK7-binding protein comprises a set of CDRs:VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein theCDRs are present in a VH and a VL pair disclosed in Table 1B. In furtherembodiments, the ALK7-binding protein comprises a set of CDRs whereinthe CDRs are present in a VH and a VL pair selected from the groupconsisting of: (a) a VH sequence of SEQ ID NO:152, and a VL sequence ofSEQ ID NO:98; (b) a VH sequence of SEQ ID NO:159, and a VL sequence ofSEQ ID NO:110; and (c) a VH sequence of SEQ ID NO:165, and a VL sequenceof SEQ ID NO:171; and wherein the protein binds ALK7.

In some embodiments, the ALK7-binding protein comprises a set of CDRs:VII-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, wherein theCDRs are present in a VH and a VL pair disclosed in Table 3. In furtherembodiments, the ALK7-binding protein comprises a set of CDRs whereinthe CDRs are present in a VH and a VL pair selected from the groupconsisting of: (a) a VH sequence of SEQ ID NO:91, and a VL sequence ofSEQ ID NO:98; (b) a VH sequence of SEQ ID NO:105, and a VL sequence ofSEQ ID NO:110; (c) a VH sequence of SEQ ID NO:117, and a VL sequence ofSEQ ID NO:124; (d) a VH sequence of SEQ ID NO:128 and a VL sequence ofSEQ ID NO:135; and (d) a VH sequence of SEQ ID NO:140 and a VL sequenceof SEQ ID NO:148; and wherein the protein binds ALK7.

In some embodiments an ALK7-binding protein comprises a set of CDRs: (a)VH-CDR1, VH-CDR2, and VH-CDR3, or (b) VL-CDR1, VL-CDR2, and VL-CDR3,wherein the set of CDRs is identical to, or has a total of one, two,three, four, five, six, seven, eight, nine, ten, or fewer than ten,amino acid substitutions, deletions, and/or insertions from a referenceset of CDRs disclosed herein. In further embodiments, the ALK7-bindingprotein comprises a set of CDRs, wherein the set of CDRs is identicalto, or has a total of one, two, three, four, five, six, seven, eight,nine, ten, or fewer than ten, amino acid substitutions, deletions,and/or insertions from a reference set of CDRs in a VH or VL sequencedisclosed in Table 1A.

In some embodiments an ALK7-binding protein comprises a set of CDRs: (a)VH-CDR1, VH-CDR2, and VH-CDR3, or (b) VL-CDR1, VL-CDR2, and VL-CDR3,wherein the set of CDRs is identical to, or has a total of one, two,three, four, five, six, seven, eight, nine, ten, or fewer than ten,amino acid substitutions, deletions, and/or insertions from a referenceset of CDRs disclosed herein. In further embodiments, the ALK7-bindingprotein comprises a set of CDRs, wherein the set of CDRs is identicalto, or has a total of one, two, three, four, five, six, seven, eight,nine, ten, or fewer than ten, amino acid substitutions, deletions,and/or insertions from a reference set of CDRs in a VH or VL sequencedisclosed in Table 1B.

In some embodiments an ALK7-binding protein comprises a set of CDRs:VII-CDR1, VH-CDR2, VII-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein theset of CDRs is identical to, or has a total of one, two, three, four,five, six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsdisclosed herein. In further embodiments, the ALK7-binding proteincomprises a set of CDRs, wherein the set of CDRs is identical to, or hasa total of one, two, three, four, five, six, seven, eight, nine, ten, orfewer than ten, amino acid substitutions, deletions, and/or insertionsfrom a reference set of CDRs in a VH and VL sequence pair disclosed inTable 3.

In additional embodiments, the ALK7-binding protein specifically bindsALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1,VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to, or has atotal of one, two, three, four, five, six, seven, eight, nine, ten, orfewer than ten, amino acid substitutions, deletions, and/or insertionsfrom a reference set of CDRs in which: (a)(i) VH-CDR1 comprises theamino acid sequence of SEQ ID NO: 1; (ii) VH-CDR2 comprises the aminoacid sequence of SEQ ID NO:2; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:3; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO:10; (v) VL-CDR2 comprises the amino acid sequence of SEQ IDNO:11; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO:12; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19;(ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20; (iii)VH-CDR3 comprises the amino acid sequence of SEQ ID NO:21; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:28; (v) VL-CDR2 comprisesthe amino acid sequence of SEQ ID NO:29; and (vi) VL-CDR3 comprises theamino acid sequence of SEQ ID NO:30; (c)(i) VH-CDR1 comprises the aminoacid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acidsequence of SEQ ID NO:38; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:39; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO:46; (v) VL-CDR2 comprises the amino acid sequence of SEQ IDNO:47; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO:48; or (d)(i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:55; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:56;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO:64; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:65; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:66; and wherein theprotein binds to ALK7. In further embodiments, the ALK7-binding proteinhas at least one characteristic selected from the group consisting of:(a) decreases the formation of a complex containing ALK7, a type IIreceptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the type IIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis) and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, theALK7-binding protein increases lipolysis by 5% to 100%, 10% to 80%, or10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in adipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%.In some embodiments, the ALK7-binding protein increase lipolysis in alipolysis assay using adipocyte cells (e.g., white adipocytes) by 5% to100%, 10% to 80%, or 10% to 60%. In further embodiments the lipolysisassay is performed in the presence of one or more ALK7 ligands selectedfrom the group consisting of: GDF1, GDF3, GDF8, activin B, activin A/B,and Nodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4of the above characteristics. In some embodiments, the ALK7-bindingprotein has at least 2, at least 3, or at least 4, of the abovecharacteristics.

In additional embodiments, the ALK7-binding protein specifically bindsALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1,VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to, or has atotal of one, two, three, four, five, six, seven, eight, nine, ten, orfewer than ten, amino acid substitutions, deletions, and/or insertionsfrom a reference set of CDRs in which: (a)(i) VH-CDR1 comprises theamino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the aminoacid sequence of SEQ ID NO:56; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:90; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ IDNO:96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO:97; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:156; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:157;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:184; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 107; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO: 108; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:109; and (c)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprisesthe amino acid sequence of SEQ ID NO:163; (iii) VH-CDR3 comprises theamino acid sequence of SEQ ID NO:164; (iv) VL-CDR1 comprises the aminoacid sequence of SEQ ID NO:167; (v) VL-CDR2 comprises the amino acidsequence of SEQ ID NO:168; and (vi) VL-CDR3 comprises the amino acidsequence of SEQ ID NO:169; and wherein the protein binds to ALK7. Infurther embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the type II receptor in the presence of theone or more TGF-beta superfamily ligands; (b) competes with one or moretype II receptors for binding to ALK7; (c) competes with one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) for binding to ALK7; (d) decreases the phosphorylationof ALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIAor ActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis)and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK7-binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In additional embodiments, the ALK7-binding protein specifically bindsALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1,VL-CDR2, and VL-CDR3, wherein the set of CDRs is identical to, or has atotal of one, two, three, four, five, six, seven, eight, nine, ten, orfewer than ten, amino acid substitutions, deletions, and/or insertionsfrom a reference set of CDRs in which: (a)(i) VH-CDR1 comprises theamino acid sequence of SEQ ID NO:88; (ii) VH-CDR2 comprises the aminoacid sequence of SEQ ID NO:89; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:90; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ IDNO:96; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO:97; (b)(i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:103;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 107; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:108; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO: 109; (c)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:114; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:115; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO: 116; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:121; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:122; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:123; (d)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:125; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:126; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:127; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:132; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:133; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:134; or (e)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:138; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO: 139; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO: 145; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:146; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:147; and wherein theprotein binds to ALK7. In further embodiments, the ALK7-binding proteinhas at least one characteristic selected from the group consisting of:(a) decreases the formation of a complex containing ALK7, a type IIreceptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the type IIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis) and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, theALK7-binding protein increases lipolysis by 5% to 100%, 10% to 80%, or10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in adipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%.In some embodiments, the ALK7-binding protein increase lipolysis in alipolysis assay using adipocyte cells (e.g., white adipocytes) by 5% to100%, 10% to 80%, or 10% to 60%. In further embodiments the lipolysisassay is performed in the presence of one or more ALK7 ligands selectedfrom the group consisting of: GDF1. GDF3, GDF8, activin B, activin A/B,and Nodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4of the above characteristics. In some embodiments, the ALK7-bindingprotein has at least 2, at least 3, or at least 4, of the abovecharacteristics.

In additional embodiments, the ALK7-binding protein specifically bindsALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1,VH-CDR2, and VL-CDR3, wherein: (a)(i) VH-CDR1 comprises the amino acidsequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequenceof SEQ ID NO:2; (iii) VH-CDR3 comprises the amino acid sequence of SEQID NO:3; (iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10;(v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 11; and (vi)VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12; (b)(i)VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19; (ii) VH-CDR2comprises the amino acid sequence of SEQ TD NO:20; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:21; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:28; (v) VL-CDR2 comprisesthe amino acid sequence of SEQ ID NO:29; and (vi) VL-CDR3 comprises theamino acid sequence of SEQ ID NO:30; (c)(i) VH-CDR1 comprises the aminoacid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acidsequence of SEQ ID NO:38; (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:39; (iv) VL-CDR1 comprises the amino acid sequenceof SEQ ID NO:46; (v) VL-CDR2 comprises the amino acid sequence of SEQ IDNO:47; and (vi) VL-CDR3 comprises the amino acid sequence of SEQ IDNO:48; or (d)(i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:55; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:56;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO:64; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:65; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:66; and wherein theprotein binds ALK7.

In additional embodiments, the ALK7-binding protein specifically bindsALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (a)(i) VH-CDR1 comprises the amino acidsequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequenceof SEQ ID NO:56; (iii) VH-CDR3 comprises the amino acid sequence of SEQID NO:90; (iv) VL-CDR1 comprises the amino acid sequence of SEQ IDNO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:96;and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:97;(b)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:156; (ii)VH-CDR2 comprises the amino acid sequence of SEQ ID NO:157; (iii)VH-CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:107; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:108; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:109; and (c)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprisesthe amino acid sequence of SEQ ID NO:163; (iii) VH-CDR3 comprises theamino acid sequence of SEQ ID NO:1164; (iv) VL-CDR1 comprises the aminoacid sequence of SEQ ID NO:107; (v) VL-CDR2 comprises the amino acidsequence of SEQ ID NO: 168; and (vi) VL-CDR3 comprises the amino acidsequence of SEQ ID NO:169; and wherein the protein binds ALK7.

In additional embodiments, the ALK7-binding protein specifically bindsALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (a)(i) VH-CDR1 comprises the amino acidsequence of SEQ ID NO:88; (ii) VH-CDR2 comprises the amino acid sequenceof SEQ ID NO:89; (iii) VH-CDR3 comprises the amino acid sequence of SEQID NO:90; (iv) VL-CDR1 comprises the amino acid sequence of SEQ IDNO:95; (v) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:96:and (vi) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:97;(b)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 102; (ii)VH-CDR2 comprises the amino acid sequence of SEQ ID NO:103; (iii)VH-CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:107; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:108; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:109; (c)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO: 114; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:115; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:116; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:121; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:122; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:123; (d)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:125; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:126; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:127; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:132; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:133; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:134; or (e)(i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:137; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:138; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO: 139; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:145; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO: 146; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO: 147; and wherein theprotein binds ALK7.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs that has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than ten, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:2; (iii)VH-CDR3 comprises the amino acid sequence of SEQ ID NO:3; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:10; (v) VL-CDR2 comprisesthe amino acid sequence of SEQ ID NO: 11; and (vi) VL-CDR3 comprises theamino acid sequence of SEQ ID NO:12; and wherein the protein binds ALK7.In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and activin B on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with ActRIIA or ActRIIB) for bindingto ALK7; (c) competes with one or more TGF-beta superfamily ligands(e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for bindingto ALK7; (d) decreases the phosphorylation of ALK7 in cells expressingALK7 and an ActRII receptor (e.g., ActRIIA or ActRIIB) in the presenceof GDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e) decreasesthe phosphorylation of Smads (e.g., Smad2 and/or Smad3) in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) inthe presence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs that has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than ten, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:21; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO:28; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:29; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:30; and wherein theprotein binds ALK7. In further embodiments, the ALK7-binding protein hasat least one characteristic selected from the group consisting of: (a)decreases the formation of a complex containing ALK7, a A type IIreceptor (e.g., ActRIIA or ActRIIB), and activin B on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and an ActRII receptor (e.g., ActRIIA orActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin A/B,and/or Nodal; (e) decreases the phosphorylation of Smads (e.g., Smad2and/or Smad3) in cells expressing ALK7 and a type II receptor (e.g.,ActRIIA and/or ActRIIB) in the presence of one or more TGF-beta ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) bindsto ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE®analysis), and (g) decreases the formation of a complex containing ALK7,a co-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs that has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than ten, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37;(ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; (iii)VH-CDR3 comprises the amino acid sequence of SEQ ID NO:39; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:46; (v) VL-CDR2 comprisesthe amino acid sequence of SEQ ID NO:47; and (vi) VL-CDR3 comprises theamino acid sequence of SEQ ID NO:48; and wherein the protein binds ALK7.In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and an ActRII receptor (e.g., ActRIIA orActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin A/B,and/or Nodal; (e) decreases the phosphorylation of Smads (e.g., Smad2and/or Smad3) in cells expressing ALK7 and a type II receptor (e.g.,ActRIIA and/or ActRIIB) in the presence of one or more TGF-beta ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) bindsto ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE®analysis), and (g) decreases the formation of a complex containing ALK7,a co-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs that has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than ten, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:55;(ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:56; (iii)VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:64; (v) VL-CDR2 comprisesthe amino acid sequence of SEQ ID NO:65; and (vi) VL-CDR3 comprises theamino acid sequence of SEQ ID NO:66; and wherein the protein binds ALK7.In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and an ActRII receptor (e.g., ActRIIA orActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin A/B,and/or Nodal; (e) decreases the phosphorylation of Smads (e.g., Smad2and/or Smad3) in cells expressing ALK7 and a type II receptor (e.g.,ActRIIA and/or ActRIIB) in the presence of one or more TGF-beta ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) bindsto ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE®analysis), and (g) decreases the formation of a complex containing ALK7,a co-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs that has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than ten, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (a)(i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:88; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID N089;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:90: (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO:95; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:96; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:97; and wherein theprotein binds ALK7. In further embodiments, the ALK7-binding protein hasat least one characteristic selected from the group consisting of: (a)decreases the formation of a complex containing ALK7, a type II receptor(e.g., ActRIIA or ActRIIB), and activin B on the surface of cellsexpressing ALK7 and the ActRII receptor in the presence of the one ormore TGF-beta superfamily ligands; (b) competes with ActRIIA or ActRIIB)for binding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and an ActRII receptor (e.g., ActRIIA or ActRIIB) in thepresence of GDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs that has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than ten, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:103;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:104; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 107; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:108; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:109; and wherein theprotein binds ALK7. In further embodiments, the ALK7-binding protein hasat least one characteristic selected from the group consisting of: (a)decreases the formation of a complex containing ALK7, a A type IIreceptor (e.g., ActRIIA or ActRIIB), and activin B on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and an ActRII receptor (e.g., ActRIIA orActRIIB) in the presence of GDF1, GDF3, GDF8, activin B, activin A/B,and/or Nodal; (e) decreases the phosphorylation of Smads (e.g., Smad2and/or Smad3) in cells expressing ALK7 and a type II receptor (e.g.,ActRIIA and/or ActRIIB) in the presence of one or more TGF-beta ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) bindsto ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE®analysis), and (g) decreases the formation of a complex containing ALK7,a co-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs that has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than ten, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:114; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:115; (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:116;(iv) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:121; (v)VL-CDR2 comprises the amino acid sequence of SEQ ID NO:122; and (vi)VL-CDR3 comprises the amino acid sequence of SEQ ID NO:123; and whereinthe protein binds ALK7. In further embodiments, the ALK7-binding proteinhas at least one characteristic selected from the group consisting of:(a) decreases the formation of a complex containing ALK7, a type IIreceptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and an ActRII receptor (e.g., ActRIIA or ActRIIB) in the presence ofGDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e) decreasesthe phosphorylation of Smads (e.g., Smad2 and/or Smad3) in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) inthe presence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs that has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than ten, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:125; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:126;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:127; (iv)VL-CDR1 comprises the amino acid sequence of SEQ ID NO:132; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:133; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:134; and wherein theprotein binds ALK7. In further embodiments, the ALK7-binding protein hasat least one characteristic selected from the group consisting of: (a)decreases the formation of a complex containing ALK7, a type II receptor(e.g., ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands(e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on thesurface of cells expressing ALK7 and the ActRII receptor in the presenceof the one or more TGF-beta superfamily ligands; (b) competes with oneor more type II receptors for binding to ALK7; (c) competes with one ormore TGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal,GDF1, GDF3 and/or GDF8) for binding to ALK7; (d) decreases thephosphorylation of ALK7 in cells expressing ALK7 and an ActRII receptor(e.g., ActRIIA or ActRIIB) in the presence of GDF1, GDF3, GDF8, activinB, activin A/B, and/or Nodal; (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (t) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a set of CDRs that has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than ten, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:137; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:138;(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:139; (iv)VL-CDR 1 comprises the amino acid sequence of SEQ ID NO: 145; (v)VL-CDR2 comprises the amino acid sequence of SEQ ID NO:146; and (vi)VL-CDR3 comprises the amino acid sequence of SEQ ID NO:147; and whereinthe protein binds ALK7. In further embodiments, the ALK7-binding proteinhas at least one characteristic selected from the group consisting of:(a) decreases the formation of a complex containing ALK7, a type IIreceptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and an ActRII receptor (e.g., ActRIIA or ActRIIB) in the presence ofGDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e) decreasesthe phosphorylation of Smads (e.g., Smad2 and/or Smad3) in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) inthe presence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37;(ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; and(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:39 or 57;and the protein binds ALK7. In a further embodiment, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VH-CDR1,VH-CDR2, and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acidsequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequenceof SEQ ID NO:38; and (iii) VH-CDR3 comprises the amino acid sequence ofSEQ ID NO:39; and the protein binds ALK7. In a further embodiment, anALK7-binding protein specifically binds ALK7 and comprises a set ofCDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the set of CDRs isidentical to, or has a total of one, two, three, four, five, six, seven,eight, nine, ten, or fewer than ten, amino acid substitutions,deletions, and/or insertions from a reference set of CDRs in which: (i)VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:38; and (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:39; and the protein bindsALK7. In a further embodiment, an ALK7-binding protein specificallybinds ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3,wherein the set of CDRs is identical to, or has a total of one, two,three, four, five, six, seven, eight, nine, ten, or fewer than ten,amino acid substitutions, deletions, and/or insertions from a referenceset of CDRs in which: (i) VH-CDR1 comprises the amino acid sequence ofSEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ IDNO:38; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ IDNO:57; and the protein binds ALK7. In a further embodiment, anALK7-binding protein specifically binds ALK7 and comprises a set ofCDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein: (i) VH-CDR1 comprises theamino acid sequence of SEQ ID NO:37; (ii) VH-CDR2 comprises the aminoacid sequence of SEQ ID NO:38; and (iii) VH-CDR3 comprises the aminoacid sequence of SEQ ID NO:57; and the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and an ActRII receptor (e.g., ActRIIA or ActRIIB in thepresence of GDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 1;(ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:2; and (iii)VH-CDR3 comprises the amino acid sequence of SEQ ID NO:3; and theprotein binds ALK7. In some embodiments, an ALK7-binding proteinspecifically binds ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2,and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence ofSEQ ID NO:1; (ii) VH-CDR2 comprises the amino acid sequence of SEQ IDNO:2; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ IDNO:3; and the protein binds ALK7. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and an ActRII receptor (e.g., ActRIIA or ActRIIB in the presence ofGDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e) decreasesthe phosphorylation of Smads (e.g., Smad2 and/or Smad3) in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) inthe presence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:19;(ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:20; and(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:21; and theprotein binds ALK7. In some embodiments, an ALK7-binding proteinspecifically binds ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2,and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence ofSEQ ID NO:19; (ii) VH-CDR2 comprises the amino acid sequence of SEQ IDNO:20; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ IDNO:21; and the protein binds ALK7. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and an ActRII receptor (e.g., ActRIIA or ActRIIB in the presence ofGDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e) decreasesthe phosphorylation of Smads (e.g., Smad2 and/or Smad3) in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) inthe presence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, an ALK7-binding protein specifically binds ALK7and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein theset of CDRs is identical to, or has a total of one, two, three, four,five, six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:37;(ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:38; and(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:39; and theprotein binds ALK7. In a further embodiment, an ALK7-binding proteinspecifically binds ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2,and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acid sequence ofSEQ ID NO:37; (ii) VH-CDR2 comprises the amino acid sequence of SEQ IDNO:38; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ IDNO:39; and the protein binds ALK7. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and an ActRII receptor (e.g., ActRIIA or ActRIIB in the presence ofGDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e) decreasesthe phosphorylation of Smads (e.g., Smad2 and/or Smad3) in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) inthe presence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, an ALK7-binding protein specifically binds ALK7and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein theset of CDRs is identical to, or has a total of one, two, three, four,five, six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:55;(ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:56; and(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:57; and theprotein binds ALK7. In a further embodiment, an ALK7-binding proteinspecifically binds ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2,and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acid sequence ofSEQ ID NO:55; (ii) VH-CDR2 comprises the amino acid sequence of SEQ IDNO:56; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ IDNO:57; and the protein binds ALK7. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and an ActRII receptor (e.g., ActRIIA or ActRIIB in the presence ofGDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e) decreasesthe phosphorylation of Smads (e.g., Smad2 and/or Smad3) in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) inthe presence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:88;(ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:89; and(iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:90; and theprotein binds ALK7. In some embodiments, an ALK7-binding proteinspecifically binds ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2,and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence ofSEQ ID NO:88; (ii) VH-CDR2 comprises the amino acid sequence of SEQ IDNO:89; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ IDNO:90; and the protein binds ALK7. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type IT receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and an ActRII receptor (e.g., ActRIIA or ActRIIB in the presence ofGDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e) decreasesthe phosphorylation of Smads (e.g., Smad2 and/or Smad3) in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) inthe presence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 103;and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:104;and the protein binds ALK7. In some embodiments, an ALK7-binding proteinspecifically binds ALK7 and comprises a set of CDRs: VH-CDR1, VH-CDR2,and VH-CDR3, wherein: (i) VH-CDR1 comprises the amino acid sequence ofSEQ ID NO:102; (ii) VH-CDR2 comprises the amino acid sequence of SEQ IDNO:103; and (iii) VH-CDR3 comprises the amino acid sequence of SEQ IDNO:104; and the protein binds ALK7. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and an ActRII receptor (e.g., ActRIIA or ActRIIB in the presence ofGDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e) decreasesthe phosphorylation of Smads (e.g., Smad2 and/or Smad3) in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) inthe presence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, an ALK7-binding protein specifically binds ALK7and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein theset of CDRs is identical to, or has a total of one, two, three, four,five, six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ ID NO:114; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:115;and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:116;and the protein binds ALK7. In a further embodiment, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VH-CDR1,VH-CDR2, and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acidsequence of SEQ ID NO:114; (ii) VH-CDR2 comprises the amino acidsequence of SEQ ID NO:115; and (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:116; and the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type H receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and an ActRII receptor (e.g., ActRIIA or ActRIIB in thepresence of GDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, an ALK7-binding protein specifically binds ALK7and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein theset of CDRs is identical to, or has a total of one, two, three, four,five, six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:125; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:126;and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:127;and the protein binds ALK7. In a further embodiment, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VH-CDR1,VH-CDR2, and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acidsequence of SEQ ID NO:125; (ii) VH-CDR2 comprises the amino acidsequence of SEQ ID NO:126; and (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:127; and the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and an ActRII receptor (e.g., ActRIIA or ActRIIB in thepresence of GDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, an ALK7-binding protein specifically binds ALK7and comprises a set of CDRs: VH-CDR1, VH-CDR2, and VH-CDR3, wherein theset of CDRs is identical to, or has a total of one, two, three, four,five, six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VH-CDR1 comprises the amino acid sequence of SEQ IDNO:137; (ii) VH-CDR2 comprises the amino acid sequence of SEQ ID NO:138;and (iii) VH-CDR3 comprises the amino acid sequence of SEQ ID NO:139;and the protein binds ALK7. In a further embodiment, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VH-CDR1,VH-CDR2, and VH-CDR3, wherein (i) VH-CDR1 comprises the amino acidsequence of SEQ ID NO:137; (ii) VH-CDR2 comprises the amino acidsequence of SEQ ID NO:138; and (iii) VH-CDR3 comprises the amino acidsequence of SEQ ID NO:139; and the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and an ActRII receptor (e.g., ActRIIA or ActRIIB in thepresence of GDF1, GDF3, GDF8, activin B, activin A/B, and/or Nodal; (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:10;(ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 11; and(iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:12; andwherein the protein binds ALK7. In some embodiments, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acidsequence of SEQ ID NO:10; (ii) VL-CDR2 comprises the amino acid sequenceof SEQ ID NO: 11; and (iii) VL-CDR3 comprises the amino acid sequence ofSEQ ID NO:12; and wherein the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:28;(ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:29; and(iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:30; andwherein the protein binds ALK7. In some embodiments, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acidsequence of SEQ ID NO:28; (ii) VL-CDR2 comprises the amino acid sequenceof SEQ ID NO:29; and (iii) VL-CDR3 comprises the amino acid sequence ofSEQ ID NO:30; and wherein the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:46;(ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:47; and(iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:48; andwherein the protein binds ALK7. In some embodiments, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acidsequence of SEQ ID NO:46; (ii) VL-CDR2 comprises the amino acid sequenceof SEQ ID NO:47; and (iii) VL-CDR3 comprises the amino acid sequence ofSEQ ID NO:48; and wherein the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:64;(ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:65; and(iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:66; andwherein the protein binds ALK7. In some embodiments, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acidsequence of SEQ ID NO:64; (ii) VL-CDR2 comprises the amino acid sequenceof SEQ ID NO:65; and (iii) VL-CDR3 comprises the amino acid sequence ofSEQ ID NO:66; and wherein the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:95;(ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:96; and(iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:97; andwherein the protein binds ALK7. In some embodiments, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acidsequence of SEQ ID NO:95; (ii) VL-CDR2 comprises the amino acid sequenceof SEQ ID NO:96; and (iii) VL-CDR3 comprises the amino acid sequence ofSEQ ID NO:97; and wherein the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VL-CDR1 comprises the amino acid sequence of SEQ IDNO:107; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:108;and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:109;and wherein the protein binds ALK7. In some embodiments, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acidsequence of SEQ ID NO: 107; (ii) VL-CDR2 comprises the amino acidsequence of SEQ ID NO:108; and (iii) VL-CDR3 comprises the amino acidsequence of SEQ ID NO:109; and wherein the protein binds ALK7. Infurther embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%/c, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VL-CDR1 comprises the amino acid sequence of SEQ IDNO:121; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:122;and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:123;and wherein the protein binds ALK7. In some embodiments, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acidsequence of SEQ ID NO: 121; (ii) VL-CDR2 comprises the amino acidsequence of SEQ ID NO:122; and (iii) VL-CDR3 comprises the amino acidsequence of SEQ ID NO:123; and wherein the protein binds ALK7. Infurther embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActrIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VL-CDR1 comprises the amino acid sequence of SEQ ID NO:132; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:133;and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:134;and wherein the protein binds ALK7. In some embodiments, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acidsequence of SEQ ID NO: 132; (ii) VL-CDR2 comprises the amino acidsequence of SEQ ID NO:133; and (iii) VL-CDR3 comprises the amino acidsequence of SEQ ID NO:134; and wherein the protein binds ALK7. Infurther embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, an ALK7-binding protein specifically binds ALK7 andcomprises a set of CDRs: VL-CDR1, VL-CDR2, and VL-CDR3, wherein the setof CDRs is identical to, or has a total of one, two, three, four, five,six, seven, eight, nine, ten, or fewer than ten, amino acidsubstitutions, deletions, and/or insertions from a reference set of CDRsin which: (i) VL-CDR1 comprises the amino acid sequence of SEQ IDNO:145; (ii) VL-CDR2 comprises the amino acid sequence of SEQ ID NO:146;and (iii) VL-CDR3 comprises the amino acid sequence of SEQ ID NO:147;and wherein the protein binds ALK7. In some embodiments, an ALK7-bindingprotein specifically binds ALK7 and comprises a set of CDRs: VL-CDR1,VL-CDR2, and VL-CDR3, wherein: (i) VL-CDR1 comprises the amino acidsequence of SEQ ID NO:145; (ii) VL-CDR2 comprises the amino acidsequence of SEQ ID NO:146; and (iii) VL-CDR3 comprises the amino acidsequence of SEQ ID NO:147; and wherein the protein binds ALK7. Infurther embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments an ALK7-binding protein comprises a VH-CDR3 or aVL-CDR3 sequence disclosed herein. In further embodiments, theALK7-binding protein comprises a VH-CDR3 or a VL-CDR3 sequence disclosedin Table 1A. In some embodiments an ALK7-binding protein comprises aVH-CDR3 and a VL-CDR3 sequence disclosed herein. In further embodiments,the ALK7-binding protein comprises a VH-CDR3 and a VL-CDR3 sequencedisclosed in Table 1A. In some embodiments, the ALK7-binding proteincomprises a VH-CDR3 or a VL-CDR3 sequence disclosed in Table 1B. Infurther embodiments, the ALK7-binding protein comprises a VH-CDR3 and aVL-CDR3 sequence disclosed in Table 1B. In some embodiments, theALK7-binding protein comprises a VH-CDR3 or a VL-CDR3 sequence disclosedin Table 3. In further embodiments, the ALK7-binding protein comprises aVH-CDR3 and a VL-CDR3 sequence disclosed in Table 3.

In some embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR3 having the amino acid sequence of SEQ ID NO:3. Infurther embodiments the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:3 and a VH-CDR2 having the aminoacid sequence of SEQ ID NO:2. In further embodiments, the ALK7-bindingprotein comprises a VH-CDR3 having the amino acid sequence of SEQ IDNO:3, a VH-CDR2 having the amino acid sequence of SEQ ID NO:2, and aVH-CDR1 having the amino acid sequence of SEQ ID NO: 1. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR3 having the amino acid sequence of SEQ ID NO:21. Infurther embodiments the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:21 and a VH-CDR2 having the aminoacid sequence of SEQ ID NO:20. In further embodiments, the ALK7-bindingprotein comprises a VH-CDR3 having the amino acid sequence of SEQ IDNO:21, a VH-CDR2 having the amino acid sequence of SEQ ID NO:20, and aVH-CDR1 having the amino acid sequence of SEQ ID NO: 19. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:39. In further embodiments theALK7-binding protein comprises a VH-CDR3 having the amino acid sequenceof SEQ ID NO:39 and a VH-CDR2 having the amino acid sequence of SEQ IDNO:38. In further embodiments, the ALK7-binding protein comprises aVH-CDR3 having the amino acid sequence of SEQ ID NO:39, a VH-CDR2 havingthe amino acid sequence of SEQ ID NO:38, and a VH-CDR1 having the aminoacid sequence of SEQ ID NO:37. In further embodiments, the ALK7-bindingprotein has at least one characteristic selected from the groupconsisting of: (a) decreases the formation of a complex containing ALK7,a type IT receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:57. In further embodiments theALK7-binding protein comprises a VH-CDR3 having the amino acid sequenceof SEQ ID NO:57 and a VH-CDR2 having the amino acid sequence of SEQ IDNO:56. In further embodiments, the ALK7-binding protein comprises aVH-CDR3 having the amino acid sequence of SEQ ID NO:57, a VH-CDR2 havingthe amino acid sequence of SEQ ID NO:56, and a VH-CDR1 having the aminoacid sequence of SEQ ID NO:55. In further embodiments, the ALK7-bindingprotein has at least one characteristic selected from the groupconsisting of: (a) decreases the formation of a complex containing ALK7,a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:1. Infurther embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:1 and aVH-CDR2 having the amino acid sequence of SEQ ID NO:2. In furtherembodiments, the disclosure provides an ALK7-binding protein comprisinga VH-CDR1 having the amino acid sequence of SEQ ID NO:1, a VH-CDR2having the amino acid sequence of SEQ ID NO:2, and a VH-CDR3 having theamino acid sequence of SEQ ID NO:3 or 21.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR2 having the amino acid sequence of SEQ ID NO:2. Infurther embodiments the ALK7-binding protein comprises a VH-CDR2 havingthe amino acid sequence of SEQ ID NO:2 and a VH-CDR1 having the aminoacid sequence of SEQ ID NO:1. In further embodiments, the ALK7-bindingprotein comprises a VH-CDR2 having the amino acid sequence of SEQ IDNO:2, a VH-CDR1 having the amino acid sequence of SEQ ID NO:1, and aVH-CDR3 having the amino acid sequence of SEQ ID NO:3 or 21.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:38. Infurther embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:37 anda VH-CDR2 having the amino acid sequence of SEQ ID NO:38. In furtherembodiments, the disclosure provides an ALK7-binding protein comprisinga VH-CDR1 having the amino acid sequence of SEQ ID NO:37, a VH-CDR2having the amino acid sequence of SEQ ID NO:38, and a VH-CDR3 having theamino acid sequence of SEQ ID NO:39 or 57.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR2 having the amino acid sequence of SEQ ID NO:38. Infurther embodiments the ALK7-binding protein comprises a VH-CDR2 havingthe amino acid sequence of SEQ ID NO:38 and a VH-CDR1 having the aminoacid sequence of SEQ ID NO:37. In further embodiments, the ALK7-bindingprotein comprises a VH-CDR2 having the amino acid sequence of SEQ IDNO:38, a VH-CDR1 having the amino acid sequence of SEQ ID NO:37, and aVH-CDR3 having the amino acid sequence of SEQ ID NO:39 or 57.

In some embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR3 having the amino acid sequence of SEQ ID NO:90. Infurther embodiments the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:90 and a VH-CDR2 having the aminoacid sequence of SEQ ID NO:89. In further embodiments, the ALK7-bindingprotein comprises a VH-CDR3 having the amino acid sequence of SEQ IDNO:90, a VH-CDR2 having the amino acid sequence of SEQ ID NO:89, and aVH-CDR1 having the amino acid sequence of SEQ ID NO:88. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR3 having the amino acid sequence of SEQ ID NO:104. Infurther embodiments the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO: 104 and a VH-CDR2 having the aminoacid sequence of SEQ ID NO: 103. In further embodiments, theALK7-binding protein comprises a VH-CDR3 having the amino acid sequenceof SEQ ID NO:104, a VH-CDR2 having the amino acid sequence of SEQ IDNO:103, and a VH-CDR1 having the amino acid sequence of SEQ ID NO:102.In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO: 116. In further embodiments theALK7-binding protein comprises a VH-CDR3 having the amino acid sequenceof SEQ ID NO: 116 and a VH-CDR2 having the amino acid sequence of SEQ IDNO:115. In further embodiments, the ALK7-binding protein comprises aVH-CDR3 having the amino acid sequence of SEQ ID NO: 116, a VH-CDR2having the amino acid sequence of SEQ ID NO: 115, and a VH-CDR1 havingthe amino acid sequence of SEQ ID NO: 114. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (t) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:127. In further embodiments theALK7-binding protein comprises a VH-CDR3 having the amino acid sequenceof SEQ ID NO: 127 and a VH-CDR2 having the amino acid sequence of SEQ IDNO:126. In further embodiments, the ALK7-binding protein comprises aVH-CDR3 having the amino acid sequence of SEQ ID NO: 127, a VH-CDR2having the amino acid sequence of SEQ ID NO: 126, and a VH-CDR1 havingthe amino acid sequence of SEQ ID NO: 125. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR3 having the amino acid sequence of SEQ ID NO:164. Infurther embodiments the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:164 and a VH-CDR2 having the aminoacid sequence of SEQ ID NO: 138 or 163. In further embodiments, theALK7-binding protein comprises a VH-CDR3 having the amino acid sequenceof SEQ ID NO:164, a VH-CDR2 having the amino acid sequence of SEQ IDNO:103, and a VH-CDR1 having the amino acid sequence of SEQ ID NO:1 or137. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VH-CDR3 havingthe amino acid sequence of SEQ ID NO: 139. In further embodiments theALK7-binding protein comprises a VH-CDR3 having the amino acid sequenceof SEQ ID NO: 139 and a VH-CDR2 having the amino acid sequence of SEQ IDNO: 138. In further embodiments, the ALK7-binding protein comprises aVH-CDR3 having the amino acid sequence of SEQ ID NO:139, a VH-CDR2having the amino acid sequence of SEQ ID NO:138, and a VH-CDR1 havingthe amino acid sequence of SEQ ID NO:137. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type IT receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:88. Infurther embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:88 anda VH-CDR2 having the amino acid sequence of SEQ ID NO:89. In furtherembodiments, the disclosure provides an ALK7-binding protein comprisinga VH-CDR1 having the amino acid sequence of SEQ ID NO:88, a VH-CDR2having the amino acid sequence of SEQ ID NO:89, and a VH-CDR3 having theamino acid sequence of SEQ ID NO:90.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR2 having the amino acid sequence of SEQ ID NO:89. Infurther embodiments the ALK7-binding protein comprises a VH-CDR2 havingthe amino acid sequence of SEQ ID NO:89 and a VH-CDR1 having the aminoacid sequence of SEQ ID NO:88. In further embodiments, the ALK7-bindingprotein comprises a VH-CDR2 having the amino acid sequence of SEQ IDNO:89, a VH-CDR1 having the amino acid sequence of SEQ ID NO:88, and aVH-CDR3 having the amino acid sequence of SEQ ID NO:90.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO: 102.In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:102 anda VH-CDR2 having the amino acid sequence of SEQ ID NO:103. In furtherembodiments, the disclosure provides an ALK7-binding protein comprisinga VH-CDR1 having the amino acid sequence of SEQ ID NO: 102, a VH-CDR2having the amino acid sequence of SEQ ID NO:103, and a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:104.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR2 having the amino acid sequence of SEQ ID NO:103. Infurther embodiments the ALK7-binding protein comprises a VH-CDR2 havingthe amino acid sequence of SEQ ID NO:103 and a VH-CDR1 having the aminoacid sequence of SEQ ID NO:102. In further embodiments, the ALK7-bindingprotein comprises a VH-CDR2 having the amino acid sequence of SEQ IDNO:103, a VH-CDR1 having the amino acid sequence of SEQ ID NO:102, and aVH-CDR3 having the amino acid sequence of SEQ ID NO:104.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO: 114.In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO: 114and a VH-CDR2 having the amino acid sequence of SEQ ID NO:115. Infurther embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO: 114, aVH-CDR2 having the amino acid sequence of SEQ ID NO:115, and a VH-CDR3having the amino acid sequence of SEQ ID NO:116.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR2 having the amino acid sequence of SEQ ID NO: 115.In further embodiments the ALK7-binding protein comprises a VH-CDR2having the amino acid sequence of SEQ ID NO:115 and a VH-CDR1 having theamino acid sequence of SEQ ID NO:114. In further embodiments, theALK7-binding protein comprises a VH-CDR2 having the amino acid sequenceof SEQ ID NO:115, a VH-CDR1 having the amino acid sequence of SEQ ID NO:114, and a VH-CDR3 having the amino acid sequence of SEQ ID NO:116.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:125. Infurther embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:125 anda VH-CDR2 having the amino acid sequence of SEQ ID NO:126. In furtherembodiments, the disclosure provides an ALK7-binding protein comprisinga VH-CDR1 having the amino acid sequence of SEQ ID NO:125, a VH-CDR2having the amino acid sequence of SEQ ID NO:126, and a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:127.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR2 having the amino acid sequence of SEQ ID NO:126. Infurther embodiments the ALK7-binding protein comprises a VH-CDR2 havingthe amino acid sequence of SEQ ID NO:126 and a VH-CDR1 having the aminoacid sequence of SEQ ID NO:125. In further embodiments, the ALK7-bindingprotein comprises a VH-CDR2 having the amino acid sequence of SEQ IDNO:126, a VH-CDR1 having the amino acid sequence of SEQ ID NO: 125, anda VH-CDR3 having the amino acid sequence of SEQ ID NO: 127.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR having the amino acid sequence of SEQ ID NO:137. Infurther embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR1 having the amino acid sequence of SEQ ID NO:137 anda VH-CDR2 having the amino acid sequence of SEQ ID NO:138. In furtherembodiments, the disclosure provides an ALK7-binding protein comprisinga VII-CDR1 having the amino acid sequence of SEQ ID NO:137, a VH-CDR2having the amino acid sequence of SEQ ID NO:138, and a VH-CDR3 havingthe amino acid sequence of SEQ ID NO:139.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-CDR2 having the amino acid sequence of SEQ ID NO:138. Infurther embodiments the ALK7-binding protein comprises a VH-CDR2 havingthe amino acid sequence of SEQ ID NO:138 and a VH-CDR1 having the aminoacid sequence of SEQ ID NO:137. In further embodiments, the ALK7-bindingprotein comprises a VH-CDR2 having the amino acid sequence of SEQ IDNO:138, a VH-CDR1 having the amino acid sequence of SEQ ID NO:137, and aVH-CDR3 having the amino acid sequence of SEQ ID NO:139.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VL-CDR3 having the amino acid sequence of SEQ ID NO:12. Infurther embodiments the ALK7-binding protein comprises a VL-CDR3 havingthe amino acid sequence of SEQ ID NO:12 and a VL-CDR2 having the aminoacid sequence of SEQ ID NO:11. In further embodiments, the ALK7-bindingprotein comprises a VL-CDR3 having the amino acid sequence of SEQ IDNO:12, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 11, and aVL-CDR1 having the amino acid sequence of SEQ ID NO: 10. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VL-CDR3 having the amino acid sequence of SEQ ID NO:30. Infurther embodiments the ALK7-binding protein comprises a VL-CDR3 havingthe amino acid sequence of SEQ ID NO:30 and a VL-CDR2 having the aminoacid sequence of SEQ ID NO:29. In further embodiments, the ALK7-bindingprotein comprises a VL-CDR3 having the amino acid sequence of SEQ IDNO:30, a VL-CDR2 having the amino acid sequence of SEQ ID NO:29, and aVL-CDR1 having the amino acid sequence of SEQ ID NO:28. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VL-CDR3 having the amino acid sequence of SEQ ID NO:48. Infurther embodiments the ALK7-binding protein comprises a VL-CDR3 havingthe amino acid sequence of SEQ ID NO:48 and a VL-CDR2 having the aminoacid sequence of SEQ ID NO:47. In further embodiments, the ALK7-bindingprotein comprises a VL-CDR3 having the amino acid sequence of SEQ IDNO:48, a VL-CDR2 having the amino acid sequence of SEQ ID NO:47, and aVL-CDR1 having the amino acid sequence of SEQ ID NO:46. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActrIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VL-CDR3 havingthe amino acid sequence of SEQ ID NO:66. In further embodiments theALK7-binding protein comprises a VL-CDR3 having the amino acid sequenceof SEQ ID NO:66 and a VL-CDR2 having the amino acid sequence of SEQ IDNO:65. In further embodiments, the ALK7-binding protein comprises aVL-CDR3 having the amino acid sequence of SEQ ID NO:66, a VL-CDR2 havingthe amino acid sequence of SEQ ID NO:65, and a VL-CDR1 having the aminoacid sequence of SEQ ID NO:64. In further embodiments, the ALK7-bindingprotein has at least one characteristic selected from the groupconsisting of: (a) decreases the formation of a complex containing ALK7,a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VL-CDR3 having the amino acid sequence of SEQ ID NO:97. Infurther embodiments the ALK7-binding protein comprises a VL-CDR3 havingthe amino acid sequence of SEQ ID NO:97 and a VL-CDR2 having the aminoacid sequence of SEQ ID NO:96. In further embodiments, the ALK7-bindingprotein comprises a VL-CDR3 having the amino acid sequence of SEQ IDNO:97, a VL-CDR2 having the amino acid sequence of SEQ ID NO:96, and aVL-CDR1 having the amino acid sequence of SEQ ID NO:95. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VL-CDR3 having the amino acid sequence of SEQ ID NO:109. Infurther embodiments the ALK7-binding protein comprises a VL-CDR3 havingthe amino acid sequence of SEQ ID NO:109 and a VL-CDR2 having the aminoacid sequence of SEQ ID NO:108. In further embodiments, the ALK7-bindingprotein comprises a VL-CDR3 having the amino acid sequence of SEQ IDNO:109, a VL-CDR2 having the amino acid sequence of SEQ ID NO:108, and aVL-CDR1 having the amino acid sequence of SEQ ID NO:107. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (t) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VL-CDR3 having the amino acid sequence of SEQ ID NO:123. Infurther embodiments the ALK7-binding protein comprises a VL-CDR3 havingthe amino acid sequence of SEQ ID NO:123 and a VL-CDR2 having the aminoacid sequence of SEQ ID NO:122. In further embodiments, the ALK7-bindingprotein comprises a VL-CDR3 having the amino acid sequence of SEQ ID NO:123, a VL-CDR2 having the amino acid sequence of SEQ ID NO:122, and aVL-CDR1 having the amino acid sequence of SEQ ID NO:121. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VL-CDR3 havingthe amino acid sequence of SEQ ID NO: 134. In further embodiments theALK7-binding protein comprises a VL-CDR3 having the amino acid sequenceof SEQ ID NO: 134 and a VL-CDR2 having the amino acid sequence of SEQ IDNO:133. In further embodiments, the ALK7-binding protein comprises aVH-CDR3 having the amino acid sequence of SEQ ID NO: 134, a VL-CDR2having the amino acid sequence of SEQ ID NO:133, and a VL-CDR1 havingthe amino acid sequence of SEQ ID NO:132. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VL-CDR3 havingthe amino acid sequence of SEQ ID NO: 147. In further embodiments theALK7-binding protein comprises a VL-CDR3 having the amino acid sequenceof SEQ ID NO: 147 and a VL-CDR2 having the amino acid sequence of SEQ IDNO:146. In further embodiments, the ALK7-binding protein comprises aVL-CDR3 having the amino acid sequence of SEQ ID NO:147, a VL-CDR2having the amino acid sequence of SEQ ID NO:146, and a VL-CDR1 havingthe amino acid sequence of SEQ ID NO:145. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In further embodiments, the disclosure provides an ALK7-binding proteincomprising a VH-antigen binding domain 3 (ABD3) having the amino acidsequence of SEQ ID NO:75, 78, 81, or 84. In one embodiment, theALK7-binding protein comprises a VH-ABD3 having the amino acid sequenceof SEQ ID NO:75. In one embodiment, the ALK7-binding protein comprises aVH-ABD3 having the amino acid sequence of SEQ ID NO:75 and a VH-antigenbinding domain 2 (VH-ABD2) having the amino acid sequence of SEQ IDNO:74. In further embodiments, the ALK7-binding protein comprises aVH-ABD3 having the amino acid sequence of SEQ ID NO:75, a VH-ABD2 havingthe amino acid sequence of SEQ ID NO:74, and a VH-antigen binding domain1 (VH-ABD1) having the amino acid sequence of SEQ ID NO:73. In oneembodiment, the ALK7-binding protein comprises a VH-ABD3 having theamino acid sequence of SEQ ID NO:75. In one embodiment, the ALK7-bindingprotein comprises a VH-ABD3 having the amino acid sequence of SEQ IDNO:75 and a VH-antigen binding domain 2 (VH-ABD2) having the amino acidsequence of SEQ ID NO:74. In further embodiments, the ALK7-bindingprotein comprises a VH-ABD3 having the amino acid sequence of SEQ IDNO:75, a VH-ABD2 having the amino acid sequence of SEQ ID NO:74, and aVH-antigen binding domain 1 (VH-ABD1) having the amino acid sequence ofSEQ ID NO:73. In one embodiment, the ALK7-binding protein comprises aVH-ABD3 having the amino acid sequence of SEQ ID NO:78. In oneembodiment, the ALK7-binding protein comprises a VH-ABD3 having theamino acid sequence of SEQ ID NO:78 and a VH-antigen binding domain 2(VH-ABD2) having the amino acid sequence of SEQ ID NO:77. In furtherembodiments, the ALK7-binding protein comprises a VH-ABD3 having theamino acid sequence of SEQ ID NO:78, a VH-ABD2 having the amino acidsequence of SEQ ID NO:77, and a VH-antigen binding domain 1 (VH-ABD1)having the amino acid sequence of SEQ ID NO:76. In one embodiment, theALK7-binding protein comprises a VH-ABD3 having the amino acid sequenceof SEQ ID NO:81. In one embodiment, the ALK7-binding protein comprises aVH-ABD3 having the amino acid sequence of SEQ ID NO:81 and a VH-antigenbinding domain 2 (VH-ABD2) having the amino acid sequence of SEQ IDNO:80. In further embodiments, the ALK7-binding protein comprises aVH-ABD3 having the amino acid sequence of SEQ ID NO:81, a VH-ABD2 havingthe amino acid sequence of SEQ ID NO:80, and a VH-antigen binding domain1 (VH-ABD1) having the amino acid sequence of SEQ ID NO:79. In oneembodiment, the ALK7-binding protein comprises a VH-ABD3 having theamino acid sequence of SEQ ID NO:84. In one embodiment, the ALK7-bindingprotein comprises a VH-ABD3 having the amino acid sequence of SEQ IDNO:84 and a VH-antigen binding domain 2 (VH-ABD2) having the amino acidsequence of SEQ ID NO:83. In further embodiments, the ALK7-bindingprotein comprises a VH-ABD3 having the amino acid sequence of SEQ IDNO:84, a VH-ABD2 having the amino acid sequence of SEQ ID NO:83, and aVH-antigen binding domain 1 (VH-ABD1) having the amino acid sequence ofSEQ ID NO:82. In further embodiments, the ALK7-binding protein has atleast one characteristic selected from the group consisting of: (a)decreases the formation of a complex containing ALK7, a type II receptor(e.g., ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands(e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on thesurface of cells expressing ALK7 and the ActRII receptor in the presenceof the one or more TGF-beta superfamily ligands; (b) competes with oneor more type II receptors for binding to ALK7; (c) competes with one ormore TGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal,GDF1, GDF3 and/or GDF8) for binding to ALK7; (d) decreases thephosphorylation of ALK7 in cells expressing ALK7 and a type II receptor(e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-beta superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (e) decreases the phosphorylation of Smads (e.g., Smad2 and/orSmad3) in cells expressing ALK7 and a type II receptor (e.g., ActRIIAand/or ActRIIB) in the presence of one or more TGF-beta ligands (e.g.,GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds toALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE®analysis), and (g) decreases the formation of a complex containing ALK7,a co-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments an ALK7-binding protein comprises a VH or a VL whichhas a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions compared to a reference VH or VL disclosed herein. Infurther embodiments, the ALK7-binding protein comprises a VH or a VLwhich has a total of one, two, three, four, five, six, seven, eight,nine, ten, fewer than fifteen, or zero, amino acid substitutions,deletions, and/or insertions compared to a reference VH or VL disclosedin Table 1B. In some embodiments an ALK7-binding protein comprises a VHand a VL pair which has a total of one, two, three, four, five, six,seven, eight, nine, ten, fewer than fifteen, or zero, amino acidsubstitutions, deletions, and/or insertions compared to a reference VHand VL pair disclosed herein. In further embodiments, the ALK7-bindingprotein comprises a VH and VL pair which has a total of one, two, three,four, five, six, seven, eight, nine, ten, fewer than fifteen, or zero,amino acid substitutions, deletions, and/or insertions compared to areference VH and VL pair disclosed in Table 1B.

In further embodiments, the ALK7-binding protein comprises a VH or a VLwhich has a total of one, two, three, four, five, six, seven, eight,nine, ten, fewer than fifteen, or zero, amino acid substitutions,deletions, and/or insertions compared to a reference VH or VL disclosedin Table 3. In further embodiments, the ALK7-binding protein comprises aVH and VL pair which has a total of one, two, three, four, five, six,seven, eight, nine, ten, fewer than fifteen, or zero, amino acidsubstitutions, deletions, and/or insertions compared to a reference VHand VL pair disclosed in Table 1B or Table 3.

In some embodiments, the ALK7-binding protein a VH and a VL pairselected from the group consisting of: (a)(i) a VH sequence having atotal of one, two, three, four, five, six, seven, eight, nine, ten,fewer than fifteen, or zero, amino acid substitutions, deletions, and/orinsertions from a reference VH sequence selected from the groupconsisting of SEQ ID NO:4, and (ii) a VL sequence having a total of one,two, three, four, five, six, seven, eight, nine, ten, fewer thanfifteen, or zero, amino acid substitutions, deletions, and/or insertionsfrom a reference VL sequence of SEQ ID NO:13; (b)(i) a VH sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VH sequence of SEQ ID NO:22, and (ii)a VL sequence having a total of one, two, three, four, five, six, seven,eight, nine, ten, fewer than fifteen, or zero, amino acid substitutions,deletions, and/or insertions from a reference VL sequence of SEQ IDNO:31; (c)(i) a VH sequence having a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:40, 170, or 171, and (ii) a VL sequence having atotal of one, two, three, four, five, six, seven, eight, nine, ten,fewer than fifteen, or zero, amino acid substitutions, deletions, and/orinsertions from a reference VL sequence of SEQ ID NO:49; and (d)(i) a VHsequence having a total of one, two, three, four, five, six, seven,eight, nine, ten, fewer than fifteen, or zero, amino acid substitutions,deletions, and/or insertions from a reference VH sequence of SEQ IDNO:58, and (ii) a VL sequence having a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VLsequence of SEQ ID NO:67; and wherein the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein a VH and a VL pairselected from the group consisting of: (a)(i) a VH sequence having atotal of one, two, three, four, five, six, seven, eight, nine, ten,fewer than fifteen, or zero, amino acid substitutions, deletions, and/orinsertions from a reference VH sequence selected from the groupconsisting of SEQ ID NO:91, and (ii) a VL sequence having a total ofone, two, three, four, five, six, seven, eight, nine, ten, fewer thanfifteen, or zero, amino acid substitutions, deletions, and/or insertionsfrom a reference VL sequence of SEQ ID NO:98; (b)(i) a VH sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VH sequence of SEQ ID NO:105, and(ii) a VL sequence having a total of one, two, three, four, five, six,seven, eight, nine, ten, fewer than fifteen, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference VL sequenceof SEQ ID NO:110; (c)(i) a VH sequence having a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VH sequence of SEQ ID NO:117, and (ii) a VL sequence having atotal of one, two, three, four, five, six, seven, eight, nine, ten,fewer than fifteen, or zero, amino acid substitutions, deletions, and/orinsertions from a reference VL sequence of SEQ ID NO: 124; (d)(i) a VHsequence having a total of one, two, three, four, five, six, seven,eight, nine, ten, fewer than fifteen, or zero, amino acid substitutions,deletions, and/or insertions from a reference VH sequence of SEQ IDNO:128, and (ii) a VL sequence having a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VLsequence of SEQ ID NO:135; and (e)(i) a VH sequence having a total ofone, two, three, four, five, six, seven, eight, nine, ten, fewer thanfifteen, or zero, amino acid substitutions, deletions, and/or insertionsfrom a reference VH sequence of SEQ ID NO:140, and (ii) a VL sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VL sequence of SEQ ID NO:148; andwherein the protein binds ALK7. In further embodiments, the ALK7-bindingprotein has at least one characteristic selected from the groupconsisting of: (a) decreases the formation of a complex containing ALK7,a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActrIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein a VH and a VL pairselected from the group consisting of: (a)(i) a VH sequence having atotal of one, two, three, four, five, six, seven, eight, nine, ten,fewer than fifteen, or zero, amino acid substitutions, deletions, and/orinsertions from a reference VH sequence selected from the groupconsisting of SEQ ID NO:152, and (ii) a VL sequence having a total ofone, two, three, four, five, six, seven, eight, nine, ten, fewer thanfifteen, or zero, amino acid substitutions, deletions, and/or insertionsfrom a reference VL sequence of SEQ ID NO:98; (b)(i) a VH sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VH sequence of SEQ ID NO: 159, and(ii) a VL sequence having a total of one, two, three, four, five, six,seven, eight, nine, ten, fewer than fifteen, or zero, amino acidsubstitutions, deletions, and/or insertions from a reference VL sequenceof SEQ ID NO:110; and (c)(i) a VH sequence having a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VH sequence of SEQ ID NO:165, and (ii) a VL sequence having atotal of one, two, three, four, five, six, seven, eight, nine, ten,fewer than fifteen, or zero, amino acid substitutions, deletions, and/orinsertions from a reference VL sequence of SEQ ID NO:171; and whereinthe protein binds ALK7. In further embodiments, the ALK7-binding proteinhas at least one characteristic selected from the group consisting of:(a) decreases the formation of a complex containing ALK7, a type IIreceptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair wherein the VH sequence has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:4; and the VL sequence has a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VL sequence of SEQ ID NO:13; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair wherein the VH sequence has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:22; and the VL sequence has a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VL sequence of SEQ ID NO:31; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair wherein the VH sequence has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:40; and the VL sequence has a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VL sequence of SEQ ID NO:49; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair wherein the VH sequence has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:58 and the VL sequence has a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VL sequence of SEQ ID NO:67; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair wherein the VH sequence has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:91; and the VL sequence has a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VL sequence of SEQ ID NO:98; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair wherein the VH sequence has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:105; and the VL sequence has a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VL sequence of SEQ ID NO:110; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TOF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair wherein the VH sequence has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO: 117; and the VL sequence has a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VL sequence of SEQ ID NO:124; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair wherein the VH sequence has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:128 and the VL sequence has a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VL sequence of SEQ ID NO:135; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB. Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair wherein the VH sequence has a total of one, two, three, four,five, six, seven, eight, nine, ten, fewer than fifteen, or zero, aminoacid substitutions, deletions, and/or insertions from a reference VHsequence of SEQ ID NO:140 and the VL sequence has a total of one, two,three, four, five, six, seven, eight, nine, ten, fewer than fifteen, orzero, amino acid substitutions, deletions, and/or insertions from areference VL sequence of SEQ ID NO:148; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (c)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal): (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 600%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VH sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VH sequence selected from the groupconsisting of (a) SEQ ID NO:4, (b) SEQ ID NO:22, (c) SEQ ID NO:40, and(d) SEQ ID NO:58; and wherein the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VH sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VH sequence selected from the groupconsisting of (a) SEQ ID NO:91, (b) SEQ ID NO:10S, (c) SEQ ID NO:117,(d) SEQ ID NO:128, and (e) SEQ ID NO:140; and wherein the protein bindsALK7. In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VL sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VL sequence of (a) SEQ ID NO:13; (b)SEQ ID NO:31; (c) SEQ ID NO:49; and (d) SEQ ID NO:67; and wherein theprotein binds ALK7. In further embodiments, the ALK7-binding protein hasat least one characteristic selected from the group consisting of: (a)decreases the formation of a complex containing ALK7, a type II receptor(e.g., ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands(e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on thesurface of cells expressing ALK7 and the ActRII receptor in the presenceof the one or more TGF-beta superfamily ligands; (b) competes with oneor more type II receptors for binding to ALK7; (c) competes with one ormore TGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal,GDF1, GDF3 and/or GDF8) for binding to ALK7; (d) decreases thephosphorylation of ALK7 in cells expressing ALK7 and a type II receptor(e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-beta superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (e) decreases the phosphorylation of Smads (e.g., Smad2 and/orSmad3) in cells expressing ALK7 and a type II receptor (e.g., ActRIIAand/or ActRIIB) in the presence of one or more TGF-beta ligands (e.g.,GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds toALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE®analysis), and (g) decreases the formation of a complex containing ALK7,a co-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein comprises a VL sequencehaving a total of one, two, three, four, five, six, seven, eight, nine,ten, fewer than fifteen, or zero, amino acid substitutions, deletions,and/or insertions from a reference VL sequence of (a) SEQ ID NO:98; (b)SEQ ID NO:110; (c) SEQ ID NO:124; (d) SEQ ID NO:135, and (e) SEQ IDNO:148; and wherein the protein binds ALK7. In further embodiments, theALK7-binding protein has at least one characteristic selected from thegroup consisting of: (a) decreases the formation of a complex containingALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and one or moreTGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal, GDF1,GDF3 and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments an ALK7-binding protein comprises a VH or a VL whichhas at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity toa reference VH or VL disclosed herein. In further embodiments, theALK7-binding protein comprises a VH or a VL which has at least 90%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to a reference VH or VLdisclosed in Table 1A. In further embodiments, the ALK7-binding proteincomprises a VH or a VL which has at least 90%, 95%, 96%, 97%, 98%, 99%,or 100% sequence identity to a reference VH or VL disclosed in Table 1B.In further embodiments, the ALK7-binding protein comprises a VH or a VLwhich has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequenceidentity to a reference VH or VL disclosed in Table 3. In someembodiments an ALK7-binding protein comprises a VH and VL which has atleast 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to areference VH and VL disclosed herein. In further embodiments, theALK7-binding protein comprises a VH and VL which has at least 90%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to a reference VH and VLdisclosed in Table 1A. In further embodiments, the ALK7-binding proteincomprises a VH and VL which has at least 90%, 95%, 96%, 97%, 98%, 99%,or 100% sequence identity to a reference VH and VL disclosed in Table1B. In further embodiments, the ALK7-binding protein comprises a VH andVL which has at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequenceidentity to a reference VH and VL disclosed in Table 3. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a VH having (a) at least 90%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to SEQ ID NO:4; (b) at least 90%, 95%, 96%, 97%,98%, 99%, or 100% sequence identity to SEQ ID NO:22; (c) at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:40; and(d) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequenceidentity to SEQ ID NO:58; and wherein the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a VH having (a) at least 90%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to SEQ ID NO:91; (b) at least 90%, 95%, 96%, 97%,98%, 99%, or 100% sequence identity to SEQ ID NO:105; (c) at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:117; (d)a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequenceidentity to SEQ ID NO:128; and (e) a VH having at least 90%, 95%, 96%,97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:140; and whereinthe protein binds ALK7. In further embodiments, the ALK7-binding proteinhas at least one characteristic selected from the group consisting of:(a) decreases the formation of a complex containing ALK7, a type IIreceptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a VL having: (a) at least 90%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to SEQ ID NO:13; (b) at least 90%, 95%, 96%, 97%,98%, 99%, or 100% sequence identity to SEQ ID NO:31; (c) at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:49; and(d) at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity toSEQ ID NO:67; and wherein the protein binds ALK7. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a VL having: (a) at least 90%, 95%, 96%, 97%, 98%, 99%, or100% sequence identity to SEQ ID NO:98; (b) at least 90%, 95%, 96%, 97%,98%, 99%, or 100% sequence identity to SEQ ID NO: 110; (c) at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:124; (d)at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQID NO:135; and (e) at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:148; and wherein the protein binds ALK7.In further embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a VH and a VL pair selected from the group consisting of:(a)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:4, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:13;(b)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:22, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:31;(c)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:40, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:49; and(d)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:58, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:67; andwherein the protein binds ALK7. In further embodiments, the ALK7-bindingprotein has at least one characteristic selected from the groupconsisting of: (a) decreases the formation of a complex containing ALK7,a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a VH and a VL pair selected from the group consisting of:(a)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO: 152, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:98;(b)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO: 159, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:110; and(c)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:165, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:171; andwherein the protein binds ALK7. In further embodiments, the ALK7-bindingprotein has at least one characteristic selected from the groupconsisting of: (a) decreases the formation of a complex containing ALK7,a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal. GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In some embodiments, the ALK7-binding protein specifically binds ALK7and comprises a VH and a VL pair selected from the group consisting of:(a)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:91, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:98;(b)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:105, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:110;(c)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO: 117, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:124;(d)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO: 128, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 135;and (e)(i) a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:140, and (ii) a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:148; andwherein the protein binds ALK7. In further embodiments, the ALK7-bindingprotein has at least one characteristic selected from the groupconsisting of: (a) decreases the formation of a complex containing ALK7,a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In some embodiments, the ALK7-binding protein has 2, 3, or 4 ofthe above characteristics. In some embodiments, the ALK7-binding proteinhas at least 2, at least 3, or at least 4, of the above characteristics.

In one embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:4, and a VL having at least 90%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:13. In oneembodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH of SEQ ID NO:4 and a VL of SEQ ID NO:13. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In one embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID SEQ ID NO:22, and a VL having at least 90%,95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:31. Inone embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH of SEQ ID SEQ ID NO:22 and a VL of SEQ ID NO:31. Infurther embodiments, the ALK7-binding protein has at least onecharacteristic selected from the group consisting of: (a) decreases theformation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal): (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In one embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:40, and a VL having at least 90%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:49. In oneembodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH of SEQ ID NO:40 and a VL of SEQ ID NO:49. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 100% to80%, or 10% to 60%. In some embodiments, the ALK7-binding proteinincrease lipolysis in a lipolysis assay using adipocyte cells (e.g.,white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In one embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:58, and a VL having at least 90%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:67. In oneembodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VII of SEQ ID NO:58 and a VL of SEQ ID NO:67. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7: (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In one embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:91, and a VL having at least 90%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:98. In oneembodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH of SEQ ID NO:91 and a VL of SEQ ID NO:98. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In one embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID SEQ ID NO: 105, and a VL having at least90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ IDNO:110. In one embodiment, the ALK7-binding protein specifically bindsALK7 and comprises a VH of SEQ ID SEQ ID NO:105 and a VL of SEQ IDNO:110. In further embodiments, the ALK7-binding protein has at leastone characteristic selected from the group consisting of: (a) decreasesthe formation of a complex containing ALK7, a type II receptor (e.g.,ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface ofcells expressing ALK7 and the ActRII receptor in the presence of the oneor more TGF-beta superfamily ligands; (b) competes with one or more typeII receptors for binding to ALK7; (c) competes with one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) for binding to ALK7; (d) decreases the phosphorylation ofALK7 in cells expressing ALK7 and a type II receptor (e.g., ActRIIA orActRIIB) in the presence of one or more TGF-beta super family ligands(e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal); (e)decreases the phosphorylation of Smads (e.g., Smad2 and/or Smad3) incells expressing ALK7 and a type II receptor (e.g., ActRIIA and/orActRIIB) in the presence of one or more TGF-beta ligands (e.g., GDF1,GDF3, GDF8, activin B, activin AB, and/or Nodal); (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In one embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:117, and a VL having at least 90%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:124. In oneembodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH of SEQ ID NO: 117 and a VL of SEQ ID NO:124. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type IT receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In one embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH having at least 90%, 95%, 96%, 97%, 98%, 99° %, or 100%sequence identity to SEQ ID NO: 128, and a VL having at least 90%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:135. In oneembodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH of SEQ TD NO:128 and a VL of SEQ ID NO:135. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In one embodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH having at least 90%, 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to SEQ ID NO:140, and a VL having at least 90%, 95%,96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:148. In oneembodiment, the ALK7-binding protein specifically binds ALK7 andcomprises a VH of SEQ ID NO:140 and a VL of SEQ ID NO:148. In furtherembodiments, the ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%4. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair selected from the group consisting of: (a) a VH sequence of SEQID NO:4 and a VL sequence of SEQ ID NO:13; (b) a VH sequence of SEQ IDNO:22, and a VL sequence of SEQ ID NO:31; (c) a VH sequence of SEQ IDNO:40, and a VL sequence of SEQ ID NO:49; and (d) a VH sequence of SEQID NO:58 and a VL sequence of SEQ ID NO:67; and wherein the proteinbinds ALK7. In further embodiments, the ALK7-binding protein has atleast one characteristic selected from the group consisting of: (a)decreases the formation of a complex containing ALK7, a type II receptor(e.g., ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands(e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on thesurface of cells expressing ALK7 and the ActRII receptor in the presenceof the one or more TGF-beta superfamily ligands; (b) competes with oneor more type II receptors for binding to ALK7; (c) competes with one ormore TGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal,GDF1, GDF3 and/or GDF8) for binding to ALK7; (d) decreases thephosphorylation of ALK7 in cells expressing ALK7 and a type II receptor(e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-beta superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (e) decreases the phosphorylation of Smads (e.g., Smad2 and/orSmad3) in cells expressing ALK7 and ActRIIA/B in the presence of GDF1,GDF3, GDF8, activin B, activin A/B, and/or Nodal; (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In a further embodiment, the ALK7-binding protein comprises a VH and aVL pair selected from the group consisting of: (a) a VH sequence of SEQID NO:91 and a VL sequence of SEQ ID NO:98; (b) a VH sequence of SEQ IDNO:105, and a VL sequence of SEQ ID NO: 110; (c) a VH sequence of SEQ IDNO:117, and a VL sequence of SEQ ID NO:124; (d) a VH sequence of SEQ IDNO:128 and a VL sequence of SEQ ID NO:135; and (e) a VH sequence of SEQID NO:140 and a VL sequence of SEQ ID NO:148; and wherein the proteinbinds ALK7. In further embodiments, the ALK7-binding protein has atleast one characteristic selected from the group consisting of: (a)decreases the formation of a complex containing ALK7, a type II receptor(e.g., ActRIIA or ActRIIB), and one or more TGF-beta superfamily ligands(e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) on thesurface of cells expressing ALK7 and the ActRII receptor in the presenceof the one or more TGF-beta superfamily ligands; (b) competes with oneor more type II receptors for binding to ALK7; (c) competes with one ormore TGF-beta superfamily ligands (e.g., activin B, activin AB, Nodal,GDF1, GDF3 and/or GDF8) for binding to ALK7; (d) decreases thephosphorylation of ALK7 in cells expressing ALK7 and a type II receptor(e.g., ActRIIA or ActRIIB) in the presence of one or more TGF-beta superfamily ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (e) decreases the phosphorylation of Smads (e.g., Smad2 and/orSmad3) in cells expressing ALK7 and ActRIIA/B in the presence of GDF1,GDF3, GDF8, activin B, activin A/B, and/or Nodal; (f) binds to ALK7 witha K_(D) of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis),and (g) decreases the formation of a complex containing ALK7, aco-receptor (e.g., cripto and/or cryptic), and one or more TGF-betasuperfamily ligands (e.g., Nodal). In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3. GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In additional embodiments an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH and a VLsequence pair disclosed herein. In additional embodiments anALK7-binding protein cross-blocks or competes for binding to ALK7 withan antibody comprising a VH and a VL sequence pair disclosed in Table1A. In some embodiments, the ALK7-binding protein specifically bindsALK7 and comprises a VH of SEQ ID NO:4, 22, 40, or 58. In additionalembodiments, the ALK7-binding protein specifically binds ALK7 andcomprises a VL of SEQ ID NO:13, 31, 49, or 67. In further embodiments,the ALK7-binding protein specifically binds ALK7 and comprises a VH ofSEQ ID NO: 4, 22, 40, or 58; and a VL of SEQ ID NO: 13, 31, 49, or 67.In certain embodiments, an ALK7-binding protein binds to the sameepitope as an ALK7-binding protein disclosed herein. In additionalembodiments, an ALK7-binding protein binds to the same epitope as anALK7-binding protein disclosed in Table 1A. The ability of anALK7-binding protein to compete for binding with and/or bind the sameepitope of ALK7 as a reference ALK7-binding protein can readily bedetermined using techniques disclosed herein or otherwise known in theart.

In additional embodiments an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH and a VLsequence pair disclosed in Table 1B. In some embodiments, theALK7-binding protein specifically binds ALK7 and comprises a VH of SEQID NO: 152, 159, or 166. In additional embodiments, the ALK7-bindingprotein specifically binds ALK7 and comprises a VL of SEQ ID NO:98, 110,or 171. In further embodiments, the ALK7-binding protein specificallybinds ALK7 and comprises a VH of SEQ ID NO: 152, 159, or 166; and a VLof SEQ ID NO: 98, 110, or 171. In certain embodiments, an ALK7-bindingprotein binds to the same epitope as an ALK7-binding protein disclosedherein. In additional embodiments, an ALK7-binding protein binds to thesame epitope as an ALK7-binding protein disclosed in Table 1A. Theability of an ALK7-binding protein to compete for binding with and/orbind the same epitope of ALK7 as a reference ALK7-binding protein canreadily be determined using techniques disclosed herein or otherwiseknown in the art.

In additional embodiments an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH and a VLsequence pair disclosed in Table 1B or Table 3. In some embodiments, theALK7-binding protein specifically binds ALK7 and comprises a VH of SEQID NO: 91, 105, 117, 128, or 140. In additional embodiments, theALK7-binding protein specifically binds ALK7 and comprises a VL of SEQID NO: 98, 110, 124, 135, or 148. In further embodiments, theALK7-binding protein specifically binds ALK7 and comprises a VH of SEQID NO: 91, 105, 117, 128, or 140; and a VL of SEQ ID NO: 98, 110, 124,135, or 148. In certain embodiments, an ALK7-binding protein binds tothe same epitope as an ALK7-binding protein disclosed herein. Inadditional embodiments, an ALK7-binding protein binds to the sameepitope as an ALK7-binding protein disclosed in Table 1A. In additionalembodiments, an ALK7-binding protein binds to the same epitope as anALK7-binding protein disclosed in Table 1B or Table 3. The ability of anALK7-binding protein to compete for binding with and/or bind the sameepitope of ALK7 as a reference ALK7-binding protein can readily bedetermined using techniques disclosed herein or otherwise known in theart.

In some embodiments, the ALK7-binding protein comprises a VH sequence ofSEQ ID NO:40 and a VL sequence of SEQ ID NO:49. In some embodiments, anALK7-binding protein cross-blocks or competes for binding to ALK7 withan antibody comprising a VH sequence of SEQ ID NO:40 and a VL sequenceof SEQ ID NO:49. In further embodiments, the ALK7-binding protein bindsthe same epitope of ALK7 as an antibody comprising a VH sequence of SEQID NO:40 and a VL sequence of SEQ ID NO:49.

In some embodiments, the ALK7-binding protein comprises a VH sequence ofSEQ ID NO:58 and a VL sequence of SEQ ID NO:67. In some embodiments, anALK7-binding protein cross-blocks or competes for binding to ALK7 withan antibody comprising a VH sequence of SEQ ID NO:58 and a VL sequenceof SEQ ID NO:67. In further embodiments, the ALK7-binding protein bindsthe same epitope of ALK7 as an antibody comprising a VH sequence of SEQID NO:58 and a VL sequence of SEQ ID NO:67.

In some embodiments, the ALK7-binding protein comprises a VH and a VLsequence of antibody J01. In some embodiments, the ALK7-binding proteincomprises a VH sequence of SEQ ID NO: 152 and a VL sequence of SEQ IDNO:98. In some embodiments, an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH sequenceof SEQ ID NO:152 and a VL sequence of SEQ ID NO:98. In furtherembodiments, the ALK7-binding protein binds the same epitope of ALK7 asan antibody comprising a VH sequence of SEQ ID NO: 152 and a VL sequenceof SEQ ID NO:98.

In some embodiments, the ALK7-binding protein comprises a VH and a VLsequence of antibody J02. In some embodiments, the ALK7-binding proteincomprises a VH sequence of SEQ ID NO:91 and a VL sequence of SEQ IDNO:98. In some embodiments, an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH sequenceof SEQ ID NO:91 and a VL sequence of SEQ ID NO:98. In furtherembodiments, the ALK7-binding protein binds the same epitope of ALK7 asan antibody comprising a VH sequence of SEQ ID NO:91 and a VL sequenceof SEQ ID NO:98.

In some embodiments, the ALK7-binding protein comprises a VH and a VLsequence of antibody K01. In some embodiments, the the ALK7-bindingprotein comprises a VH sequence of SEQ ID NO:159 and a VL sequence ofSEQ ID NO:110. In some embodiments, an ALK7-binding protein cross-blocksor competes for binding to ALK7 with an antibody comprising a VHsequence of SEQ ID NO: 159 and a VL sequence of SEQ ID NO: 110. Infurther embodiments, the ALK7-binding protein binds the same epitope ofALK7 as an antibody comprising a VH sequence of SEQ ID NO: 159 and a VLsequence of SEQ ID NO:110.

In some embodiments, the ALK7-binding protein comprises a VH and a VLsequence of antibody K02. In some embodiments, the ALK7-binding proteincomprises a VH sequence of SEQ ID NO:105 and a VL sequence of SEQ IDNO:110. In some embodiments, an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH sequenceof SEQ ID NO:105 and a VL sequence of SEQ ID NO: 110. In furtherembodiments, the ALK7-binding protein binds the same epitope of ALK7 asan antibody comprising a VH sequence of SEQ ID NO:105 and a VL sequenceof SEQ ID NO:110.

In some embodiments, the ALK7-binding protein comprises a VH and a VLsequence of antibody 004. In some embodiments, the ALK7-binding proteincomprises a VH sequence of SEQ ID NO:4 and a VL sequence of SEQ IDNO:13. In some embodiments, an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH sequenceof SEQ ID NO:4 and a VL sequence of SEQ ID NO: 13. In furtherembodiments, the ALK7-binding protein binds the same epitope of ALK7 asan antibody comprising a VII sequence of SEQ ID NO:4 and a VL sequenceof SEQ ID NO:13.

In some embodiments, the ALK7-binding protein comprises a VH and a VLsequence of antibody G05. In some embodiments, the ALK7-binding proteincomprises a VH sequence of SEQ ID NO:117 and a VL sequence of SEQ IDNO:124. In some embodiments, an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH sequenceof SEQ ID NO: 117 and a VL sequence of SEQ ID NO:124. In furtherembodiments, the ALK7-binding protein binds the same epitope of ALK7 asan antibody comprising a VH sequence of SEQ ID NO: 117 and a VL sequenceof SEQ ID NO:124.

In some embodiments, the ALK7-binding protein comprises a VH and a VLsequence of antibody C02. In some embodiments, the ALK7-binding proteincomprises a VH sequence of SEQ ID NO:22 and a VL sequence of SEQ IDNO:31. In some embodiments, an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH sequenceof SEQ ID NO:22 and a VL sequence of SEQ ID NO:31. In furtherembodiments, the ALK7-binding protein binds the same epitope of ALK7 asan antibody comprising a VH sequence of SEQ ID NO:22 and a VL sequenceof SEQ ID NO:31.

In some embodiments, the ALK7-binding protein comprises a VH and a VLsequence of antibody C03. In some embodiments, the ALK7-binding proteincomprises a VH sequence of SEQ ID NO:128 and a VL sequence of SEQ IDNO:135. In some embodiments, an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH sequenceof SEQ ID NO:128 and a VL sequence of SEQ ID NO:135. In furtherembodiments, the ALK7-binding protein binds the same epitope of ALK7 asan antibody comprising a VH sequence of SEQ ID NO: 128 and a VL sequenceof SEQ ID NO:135.

In some embodiments, the ALK7-binding protein comprises a VII and a VLsequence of antibody L01. In some embodiments, the the ALK7-bindingprotein comprises a VH sequence of SEQ ID NO:165 and a VL sequence ofSEQ ID NO:171. In some embodiments, an ALK7-binding protein cross-blocksor competes for binding to ALK7 with an antibody comprising a VHsequence of SEQ ID NO:165 and a VL sequence of SEQ ID NO:171. In furtherembodiments, the ALK7-binding protein binds the same epitope of ALK7 asan antibody comprising a VH sequence of SEQ ID NO: 165 and a VL sequenceof SEQ ID NO: 171.

In some embodiments, the ALK7-binding protein comprises a VH and a VLsequence of antibody L02. In some embodiments, the ALK7-binding proteincomprises a VH sequence of SEQ ID NO:140 and a VL sequence of SEQ IDNO:148. In some embodiments, an ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody comprising a VH sequenceof SEQ ID NO:140 and a VL sequence of SEQ ID NO:148. In furtherembodiments, the ALK7-binding protein binds the same epitope of ALK7 asan antibody comprising a VH sequence of SEQ ID NO: 140 and a VL sequenceof SEQ ID NO:148.

In some embodiments, the ALK7-binding protein is an antibody thatspecifically binds ALK7. In some embodiments, the anti-ALK7 antibody isa murine antibody, a humanized antibody, a chimeric antibody, amonoclonal antibody, a polyclonal antibody, a recombinant antibody, amultispecific antibody, or any combination thereof. In some embodimentsthe anti-ALK7 antibody is an Fv fragment, an Fab fragment, an F(ab′)2fragment, an Fab′ fragment, a dsFv fragment, an scFv fragment, or ansc(Fv)2 fragment.

In some embodiments, the ALK7-binding protein specifically binds ALK7and blocks an activity of an ALK7-ligand (e.g., GDF1, GDF3, GDF8,activin B, activin A/B, or Nodal). In some embodiments, the ALK7-bindingprotein specifically binds ALK7 and blocks an activity of a co-receptor(e.g., cripto). In some embodiments the ALK7-binding proteinspecifically binds ALK7 and decreases the fat formation associated withthe activity of an ALK7 ligand (e.g., GDF1, GDF3, GDF8, activin B,activin A/B, or Nodal). In some embodiments the ALK7-binding proteinspecifically binds ALK7 and treats or ameliorates one or more disease orconditions associated with excess weight, obesity or a metabolicdisorder. In some embodiments, the disease or condition is type IIdiabetes. In some embodiments, the disease or condition is hypertension.In some embodiments, the metabolic disorder is dyslipidemia, insulinresistance, hyperinsulinemia or hyperglycemia.

In particular embodiments, the ALK7-binding protein (e.g., an anti-ALK7antibody) decreases ALK7-mediated Smad signaling. In another embodiment,an ALK7-binding protein antagonizes ALK7-mediated inhibition oflipolysis in white and/or brown adipose cells by 5% to 100%, 10% to 95%,10 to 90%, 10 to 85%, 10 to 80%, 10 to 75%, 10 to 70%, 10 to 75%, 10 to70%, 10 to 60%, 10 to 55%, 10 to 500, or 10 to 45%, as determined in alipolysis assay. In another embodiment, an ALK7-binding protein reducesor decreases ALK7-mediated inhibition of lipolysis in white and/or brownadipose cells by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,90%, or 95%, or by about 100%, as determined in a lipolysis assay. Insome embodiments the lipolysis assay is performed in the presence of oneor more ALK7 ligands. In further embodiments, the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of GDF1, GDF3, GDF8, activin B, activin A/B, andNodal). In some embodiments the ALK7-binding protein binds ALK7 andinhibits or decreases one or more conditions associated with overweight,obesity, insulin resistance, diabetes, atherosclerosis, hypertension,inflammation, and/or NAFLD (e.g., fatty liver and/or NASH).

In particular embodiments, the ALK7-binding protein (e.g., an anti-ALK7antibody) decreases ALK7-mediated Smad signaling. In another embodiment,the ALK7-binding protein inhibits ALK7-mediated inhibition of lipolysisin white adipose cells by 5% to 100%, 10% to 95%, 10 to 90%, 10 to 85%,10 to 80%, 10 to 75%, 10 to 70%, 10 to 75%, 10 to 70%, 10 to 60%, 10 to55%, 10 to 50%, or 10 to 45%, as determined using standard techniquesand conditions in a lipolysis inhibition assay performed in the presenceof activin B (50 ng/ml) (e.g., as described in the examples herein). Inanother embodiment, an ALK7-binding protein reduces or decreasesALK7-mediated inhibition of lipolysis in white adipose cells by at least5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or by about100%, as determined, using standard techniques and conditions in alipolysis inhibition assay performed in the presence of activin B (50ng/ml) (e.g., as described in the examples herein). In some embodimentsthe ALK7-binding protein binds ALK7 and inhibits or decreases one ormore conditions associated with overweight, obesity, insulin resistance,diabetes, atherosclerosis, hypertension, inflammation, and/or NAFLD(e.g., fatty liver and/or NASH).

In certain embodiments, the blocking of ALK7 activity by an ALK7-bindingprotein (e.g., an anti-ALK7 antibody) described herein, inhibits ordecreases one or more conditions associated with excess body weight,insulin resistance, obesity or diabetes, such as hypertension, cancer,and neuropathy, retinopathy, and cardiovascular, pulmonary and kidneydisease. In further embodiments the blocking of ALK7 inhibits ordecreases one or more conditions associated with metabolic disease. Inparticular embodiments, the ALK7-binding protein (e.g., an anti-ALK7antibody) inhibits or decreases the binding to ALK7 by activin B, GDF8,or Nodal. In another embodiment the ALK7-binding protein inhibits ordecreases the inhibition of lipolysis by a Smad-dependent pathway.

As noted above, in some embodiments, an anti-ALK7 antibody (e.g., afull-length ALK7-antibody and an ALK7-binding antibody fragment, and avariant and derivative thereof) containing a VH and/or VL amino acidsequence that binds ALK7 can have at least 85%, 90%, 95%, 96%, 97%, 98%99%, or 100% sequence identity to a sequence set forth herein. In someembodiments, the VH and/or VL amino acid sequence(s) that binds ALK7comprise 8, 7, 6, 5, 4, 3, 2, 1 amino acid additions, substitutions(e.g., conservative substitutions) or deletions relative to a sequenceset forth herein. In additional embodiments, the VH and/or VL amino acidsequence that binds ALK7 comprise 1, 2, 3, 4, 5 or more amino acidadditions, substitutions (e.g., conservative substitutions) or deletionsrelative to a sequence set forth herein. An anti-ALK7 antibodycontaining VH and VL regions having a certain percent similarity to a VHregion or VL region, or having one or more substitutions, deletionsand/or insertions (e.g., conservative substitutions) can be obtained bymutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleicacid molecules encoding VH and/or VL regions described herein, followedby testing of the encoded altered antibody for binding to ALK7 andoptionally testing for retained function using the functional assaysdescribed herein or an assay known in the art that can routinely bemodified to test the retained function.

The affinity or avidity of an ALK7-binding protein such as, an anti-ALK7antibody (e.g., a full-length ALK7-antibody and an ALK7-binding antibodyfragment, and a variant and derivative thereof) for hALK7, or murALK7,can be determined experimentally using any suitable method known in theart, e.g., flow cytometry, enzyme-linked immunosorbent assay (ELISA), orradioimmunoassay (RIA), or kinetics (e.g., BIACORE® or KINEXA®analysis). Direct binding assays and competitive binding assay formatscan be readily employed. (See, for example, Berzofsky et al.,“Antibody-Antigen Interactions,” In Fundamental Immunology, Paul, W. E.,Ed., Raven Press: New York, N.Y. (1984); Kuby, Immunology, W.H. Freemanand Company: New York, N.Y. (1992); and methods described herein.) Themeasured affinity of a particular antibody-antigen interaction can varyif measured under different conditions (e.g., salt concentration, pH,temperature). Thus, measurements of affinity and other ALK7-bindingparameters (e.g., K_(D) or Kd, K_(on), K_(off)) are made withstandardized solutions of ALK7-binding proteins and ALK7 and themeasurements are performed using standardized conditions and methods, asdescribed herein or otherwise known in the art.

The disclosure further provides an ALK7-binding protein such as, ananti-ALK7 antibody as described herein, where the ALK7-binding proteinis conjugated to a heterologous agent. In certain embodiments theheterologous agent is an antimicrobial agent, a therapeutic agent, aprodrug, a peptide, a protein, an enzyme, a lipid, a biological responsemodifier, a pharmaceutical agent, a lymphokine, a heterologous antibodyor antibody fragment, a detectable label, or a polyethylene glycol(PEG). Heteroconjugate ALK7-binding proteins are discussed in moredetail elsewhere herein.

In certain embodiments, the ALK7-binding protein is not an anti-ALK7antibody. A variety of methods for identifying and producingnon-antibody polypeptides that bind with high affinity to a proteintarget are known in the art. See, e.g., Skerra, Curr. Opin. Biotech.18:295-304 (2007); Hosse et al., Protein Science 15:14-27 (2006); Gillet al., Curr. Opin. Biolechnol. 17:653-658 (2006); Nygren, FEBS J.275:2668-2676 (2008); and Skerra, FEBS J. 275:2677-2683 (2008), each ofwhich is incorporated by reference herein in its entirety. In someembodiments, phage display technology can been used to identify/producean ALK7-binding protein. In some embodiments, the ALK7-binding proteincomprises a protein scaffold based on a type selected from the groupconsisting of VASP polypeptides, avian pancreatic polypeptide (aPP),tetranectin (based on CTLD3), affilin (based onγB-crystallin/ubiquitin), a knottin, an SH3 domain, a PDZ domain,tendamistat, transferrin, an ankyrin consensus repeat domain (e.g.,DARPins), a lipocalin protein fold (e.g., anticalins and Duocalins), aProtein Epitope Mimetic (PEM), a maxybody/avimer, a domain antibody afibronectin domain (e.g., 10 Fn3, see, e.g., U.S. Appl. Publ. Nos.2003/0170753 and 20090155275, each of which is herein incorporated byreference in its entirety), a domain of protein A (e.g., Affibodies),and thioredoxin.

In some embodiments the disclosure provides an ALK7-binding protein(e.g., an anti-ALK7 antibody such as, a full-length anti-ALK7 antibodyand an ALK7-binding antibody fragment) that cross-blocks or competes forbinding ALK7 with an anti-ALK7 antibody provided herein. In someembodiments the disclosure provides an ALK7-binding protein that bindsto the same epitope of ALK7 as an ALK7-binding protein provided herein.The ability of a test ALK7-binding protein to inhibit the binding of,for example, a reference binding protein such as an antibody comprisinga VH sequence of SEQ ID NO:4 and a VL sequence of SEQ ID NO: 13, a VHsequence of SEQ ID NO:22 and a VL sequence of SEQ ID NO:31, a VHsequence of SEQ ID NO:40 and a VL sequence of SEQ ID NO:49, or a VHsequence of SEQ ID NO:58 and a VL sequence of SEQ ID NO:67, to ALK7demonstrates that the test ALK7-binding protein can compete with thereference antibody for binding to ALK7. Such an ALK7-binding proteincan, according to non-limiting theory, bind to the same or a related(e.g., a structurally similar or spatially proximal) epitope on ALK7 asthe ALK7-reference antibody with which it competes. In one embodiment,the ALK7-binding protein binds to the same epitope on ALK7 as anantibody comprising a VH sequence of SEQ ID NO:4 and a VL sequence ofSEQ ID NO: 13, a VH sequence of SEQ ID NO:22 and a VL sequence of SEQ IDNO:31, a VH sequence of SEQ ID NO:40 and a VL sequence of SEQ ID NO:49,or a VH sequence of SEQ ID NO:58 and a VL sequence of SEQ ID NO:67,respectively.

Likewise, the ability of a test ALK7-binding protein to inhibit thebinding of, for example, a reference binding protein such as an antibodycomprising a VH sequence of SEQ ID NO:91 and a VL sequence of SEQ IDNO:98, a VH sequence of SEQ ID NO:105 and a VL sequence of SEQ IDNO:110, a VH sequence of SEQ ID NO:117 and a VL sequence of SEQ IDNO:124, a VH sequence of SEQ ID NO:128 and a VL sequence of SEQ IDNO:135, or a VH sequence of SEQ ID NO:140 and a VL sequence of SEQ IDNO: 148, to ALK7 demonstrates that the test ALK7-binding protein cancompete with the reference antibody for binding to ALK7. Such anALK7-binding protein can, according to non-limiting theory, bind to thesame or a related (e.g., a structurally similar or spatially proximal)epitope on ALK7 as the ALK7-reference antibody with which it competes.In one embodiment, the ALK7-binding protein binds to the same epitope onALK7 as an antibody comprising a VH sequence of SEQ ID NO:91 and a VLsequence of SEQ ID NO:98, a VH sequence of SEQ ID NO:105 and a VLsequence of SEQ ID NO:110, a VH sequence of SEQ ID NO:117 and a VLsequence of SEQ ID NO:124, a VH sequence of SEQ ID NO:128 and a VLsequence of SEQ ID NO: 135, or a VH sequence of SEQ ID NO:140 and a VLsequence of SEQ ID NO:148, respectively.

In general, type I TGF-beta receptor family members such as, ALK7, areknown to be phosphorylated by type II receptors (e.g., ActRIIA andActRIIB) and to signal through the phosphorylation of Smads (e.g., Smad2and/or Smad3). In some embodiments, an ALK7-binding protein (e.g., ananti-ALK7 antibody) can decrease phosphorylation of ALK7 by one or moretype II receptors (e.g., ActRIIA and/or ActRIIB) in an ALK7 and type IIreceptor-expressing cell (e.g., adipocyte). In some embodiments, anALK7-binding protein (e.g., an anti-ALK7 antibody) can decreaseALK7-mediated phosphorylation of Smads (e.g., Smad2 and/or Smad3) in anALK7 and type II receptor-expressing cell (e.g., adipocyte). In someembodiments the ALK7 receptor expressing cell is murine. In someembodiments the ALK7 receptor expressing cell is human. In someembodiments the ALK7 receptor expressing cell is an adipocyte.

In some embodiments, an ALK7-binding protein has at least onecharacteristic selected from: (a) decreasing the formation of a complexcontaining ALK7, a type II receptor (e.g., ActRIIA or ActRIIB), and oneor more TGF-beta superfamily ligands (e.g., activin B, activin AB,Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressing ALK7and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competing with one or more type II receptorsfor binding to ALK7; (c) competing with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreasing the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreasing thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binding to ALK7 with a K_(D)of ≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreasing the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein has2, 3, or 4 of the above characteristics. In some embodiments, theALK7-binding protein has at least 2, at least 3, or at least 4, of theabove characteristics. In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In further embodiments, theALK7-binding protein cross-blocks or competes for binding to ALK7 withan antibody having an ALK7-binding VH and VL pair disclosed herein. Infurther embodiments, the ALK7-binding protein is an anti-ALK7 antibodyor an ALK7-binding antibody fragment.

In some embodiments, an ALK7-binding protein decreases the formation ofa complex containing ALK7, a type II receptor (e.g., ActRIIA orActRIIB), and one or more TGF-beta superfamily ligands (e.g., activin B,activin AB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cellsexpressing ALK7 and the ActRII receptor in the presence of the one ormore of the TGF-beta superfamily ligands. In some embodiments, theALK7-binding protein is an ALK7 antagonist (e.g., a neutralizinganti-ALK7 antibody). In further embodiments, the ALK-7 binding proteinincreases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in adipocytecells by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in a lipolysis assay usingadipocyte cells (e.g., white adipocytes) by 5% to 100%, 10% to 80%, or10% to 60%. In further embodiments the lipolysis assay is performed inthe presence of one or more ALK7 ligands selected from the groupconsisting of: GDF1, GDF3, GDF8, activin B, activin A/B, and Nodal. Infurther embodiments, the ALK7-binding protein cross-blocks or competesfor binding to ALK7 with an antibody having an ALK7-binding VH and VLpair disclosed herein. In further embodiments, the ALK7-binding proteinis an anti-ALK7 antibody or an ALK7-binding antibody fragment.

In some embodiments, an ALK7-binding competes with one or more type IIreceptors for binding to ALK7. In some embodiments, the ALK7-bindingprotein is an ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody).In further embodiments, the ALK-7 binding protein increases lipolysis by5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in adipocyte cells by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in a lipolysis assay using adipocyte cells(e.g., white adipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. Infurther embodiments the lipolysis assay is performed in the presence ofone or more ALK7 ligands selected from the group consisting of: GDF1,GDF3, GDF8, activin B, activin A/B, and Nodal. In further embodiments,the ALK7-binding protein cross-blocks or competes for binding to ALK7with an antibody having an ALK7-binding VH and VL pair disclosed herein.In further embodiments, the ALK7-binding protein is an anti-ALK7antibody or an ALK7-binding antibody fragment.

In some embodiments, an ALK7-binding protein (e.g., an anti-ALK7antibody) decreases the phosphorylation of Smads (e.g., Smad2 and/orSmad3) in cells expressing ALK7 and a type II receptor (e.g., ActRIIAand/or ActRIIB) in the presence of one or more TGF-beta ligands (e.g.,GDF1, GDF3, GDF8, activin B, activin AB, and/or Nodal). In someembodiments, the ALK7-binding protein decreases the phosphorylation ofSmads as measured using a cell-based assay. In some embodiments, anALK7-binding protein decreases ALK7-mediated phosphorylation with anIC₅₀ lower than 500 pM, lower than 350 pM, lower than 250 pM, lower than150 pM, lower than 100 pM, lower than 75 pM, lower than 60 pM, lowerthan 50 pM, lower than 40 pM, lower than 30 pM, lower than 20 pM, lowerthan 15 pM, lower than 10 pM, or lower than 5 pM, as measured using acell-based assay. In some embodiments, the ALK7-binding protein is anALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In further embodiments, theALK7-binding protein cross-blocks or competes for binding to ALK7 withan antibody having an ALK7-binding VH and VL pair disclosed herein. Infurther embodiments, the ALK7-binding protein is an anti-ALK7 antibodyor an ALK7-binding antibody fragment.

In some embodiments, an ALK7-binding protein binds to ALK7 with a K_(D)of ≤1 nM and ≥1l pM (e.g., as determined by BIACORE® analysis). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In further embodiments, the ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody having an ALK7-binding VHand VL pair disclosed herein. In further embodiments, the ALK7-bindingprotein is an anti-ALK7 antibody or an ALK7-binding antibody fragment.

In some embodiments, an ALK7-binding protein decreases the formation ofa complex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the ALK7-binding protein is an ALK7 antagonist (e.g., aneutralizing anti-ALK7 antibody). In further embodiments, the ALK-7binding protein increases lipolysis by 5% to 100%, 10% to 80%, or 10% to60%. In some embodiments, the ALK7-binding protein increase lipolysis inadipocyte cells by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in a lipolysisassay using adipocyte cells (e.g., white adipocytes) by 5% to 100%, 10%to 80%, or 10% to 60%. In further embodiments the lipolysis assay isperformed in the presence of one or more ALK7 ligands selected from thegroup consisting of: GDF1, GDF3, GDF8, activin B, activin A/B, andNodal. In further embodiments, the ALK7-binding protein cross-blocks orcompetes for binding to ALK7 with an antibody having an ALK7-binding VHand VL pair disclosed herein. In further embodiments, the ALK7-bindingprotein is an anti-ALK7 antibody or an ALK7-binding antibody fragment.

Preparation of ALK7-Binding Proteins

In some embodiments, the ALK7-binding protein binds the extracellulardomain of ALK7. In further embodiments, the ALK7-binding protein is ananti-ALK7 antibody such as, a full-length anti-ALK7 antibody or anALK7-binding antibody fragment, and variants, and derivatives thereof.

ALK7-binding proteins can be readily prepared using known techniques.Monoclonal anti-ALK7 antibodies can be prepared using techniques knownin the art, including hybridoma methods, such as those described byKohler and Milstein, Nature 256:495-497 (1975). Using the hybridomamethod, a mouse, hamster, or other appropriate host animal, is immunizedas described above to elicit the production by lymphocytes of antibodiesthat will specifically bind to an immunizing antigen. Lymphocytes canalso be immunized in vitro. Following immunization, the lymphocytes areisolated and fused with a suitable myeloma cell line to form hybridomacells that can then be selected away from unfused lymphocytes andmyeloma cells. Hybridomas that produce monoclonal antibodies directedspecifically against ALK7 such as hALK7, as determined byimmunoprecipitation, immunoblotting, or by an in vitro binding assay(e.g., radioimmunoassay (RIA); enzyme-linked immunosorbent assay(ELISA)) can then be propagated either in in vitro culture usingstandard methods (see, e.g., Goding, Monoclonal Antibodies: Principlesand Practice, Academic Press, 1986) or in vivo as ascites tumors in ananimal. The monoclonal antibodies can then be purified from the culturemedium or ascites fluid as described for polyclonal antibodies above.

The provided monoclonal antibodies can also be made using recombinantDNA methods as described in U.S. Pat. No. 4,816,567, wherein thepolynucleotides encoding a monoclonal antibody are isolated from matureB-cells or a hybridoma cell, such as by RT-PCR using oligonucleotideprimers that specifically amplify the genes encoding the heavy and lightchains of the antibody, and their sequence is determined using knownprocedures. The isolated polynucleotides encoding the heavy and lightchains are then cloned into suitable expression vectors, which whentransfected into host cells such as E. coli cells, simian COS cells,Chinese hamster ovary (CHO) cells, Per.C6 cells, or myeloma cells (e.g.,NS0 cells) that do not otherwise produce immunoglobulin protein,monoclonal antibodies are generated by the host cells. Recombinantanti-ALK7 monoclonal antibodies can also readily be isolated from phagedisplay libraries expressing CDRs of the desired species using knowntechniques (see, e.g., McCafferty et al., Nature 348:552-554 (1990);Clackson et al., Nature 352:624-628 (1991); and Marks et al., J. Mol.Biol. 222:581-597 (1991)).

The anti-ALK7 antibodies can optionally be humanized, resurfaced, andengineered to display high affinity for the ALK7 antigen and otherfavorable biological properties. For example, a humanized (or human)anti-ALK7 antibody, can readily be designed and prepared using commonlyavailable three-dimensional immunoglobulin modeling and known proceduresfor selecting framework (FW) residues, consensus sequences, and germlinesequences to provide a desired antibody characteristic, such asincreased affinity for ALK7.

Affinity maturation strategies and chain shuffling strategies are knownin the art and can be employed to generate high affinity anti-ALK7antibodies as well as derivatives and variants of the ALK7-bindingproteins disclosed herein. See, e.g., Marks et al., Bio/Technology10:779-783 (1992), which is herein incorporated by reference in itsentirety. An additional strategy for generating high affinity anti-ALK7antibodies as well as derivatives and variants of the ALK7-bindingproteins disclosed herein is to generate novel VH or VL regions carryingCDR-derived sequences of the disclosure using random mutagenesis of oneor more selected VH and/or VL genes to generate mutations within theentire variable domain. Such a technique that uses error-prone PCR isdescribed by Gram et al. (PNAS USA 89:3576-3580 (1992)). In someembodiments, one or two amino acid substitutions are made within a setof VH CDRs and/or VL CDRs. A further strategy used direct mutagenesis toCDR regions of VH or VL genes encoding anti-ALK7 antibodies disclosedherein. Examples of such techniques are disclosed by Barbas et al. (PNASUSA 91:3809-3813 (1994)) and Schier et al. (J. Mol. Biol. 263:551-567(1996)).

Humanization, resurfacing or engineering of anti-ALK7 antibodies of thedisclosure can be performed using any known method including, but notlimited to, those described in Jones et al., Nature 321:522 (1986);Riechmann et al., Nature 332:323 (1988); Verhoeyen et al., Science239:1534 (1988)), Sims et al., J. Immunol. 151: 2296 (1993); Chothia etal., J. Mol. Biol. 196:901 (1987), Carter et al., PNAS USA 89:4285(1992); Presta et al., J. Immunol. 151:2623 (1993), U.S. Pat. Nos.5,639,641, 5,723,323; 5,976,862; 5,824,514; 5,817,483; 5,814,476;5,763,192; 5,723,323; 5,766,886; 5,714,352; 6,204,023; 6,180,370;5,693,762; 5,530,101; 5,585,089; 5,225,539; 4,816,567, 7,557,189;7,538,195; and 7,342,110; Intl. Appl. Nos. PCT/US98/16280;PCT/US96/18978; PCT/US91/09630; PCT/US91/05939; PCT/US94/01234;PCT/GB89/01334; PCT/GB91/01134; PCT/GB92/01755; Intl. Appl. Publ. Nos.WO90/14443; WO90/14424; WO90/14430; and EP Pat. Publ. No. EP 229246;each of which is herein incorporated by reference in is entirely.Likewise, known assays are available for readily selectinganti-ALK7-antibodies displaying desirable features (e.g., assays fordetermining binding affinity to ALK7; cross-blocking assays such as theBIACORE®-based human ALK7-binding protein competition binding assaysdescribed herein).

Methods for engineering, humanizing or resurfacing non-human or humanantibodies can also be used and are known in the art. A humanized,resurfaced or similarly engineered antibody can have one or more aminoacid residues from a source that is non-human, e.g., but not limited to,mouse, rat, rabbit, non-human primate or other mammal. These non-humanamino acid residues are replaced by residues that are often referred toas “import” residues, which are typically taken from an “import”variable, constant or other domain of a known human sequence. Suchimported sequences can be used to reduce immunogenicity or reduce,enhance or modify binding, affinity, on-rate, off-rate, avidity,specificity, half-life, or any other suitable characteristic, as knownin the art. Preferably, part or all of the non-human or human CDRsequences are maintained while the non-human sequences of the variableand constant regions can be replaced with human or other amino acids.

Nucleic acid(s) encoding an ALK7-binding protein, such as a full-lengthanti-ALK7 antibody can further be modified in a number of differentmanners using recombinant DNA technology to generate alternativeantibodies. In some embodiments, nucleic acid(s) encoding the constantdomains of the light and heavy chains of, for example, a mousemonoclonal antibody can be substituted (a) for those coding regions of,for example, a human antibody to generate a chimeric antibody or (b) fornon-immunoglobulin encoding nucleic acid(s) to generate a fusionantibody. In some embodiments, the constant regions are truncated orremoved to generate the desired antibody fragment of a monoclonalantibody. Site-directed or high-density mutagenesis of the variableregion coding sequence can be used to optimize specificity, affinity,etc. of a monoclonal antibody.

Anti-ALK7 human antibodies can be directly prepared using any of thenumerous techniques known in the art. (See, e.g., Cole et al.,Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985);Boemer et al., J. Immunol. 147(1):86-95 (1991); and U.S. Pat. No.5,750,373). Similarly, human anti-ALK7 antibodies can readily beobtained from immortalized human B lymphocyte immunized in vitro orisolated from an immunized individual that produces an antibody directedagainst ALK7.

Human anti-ALK7 antibodies can also be selected from a phage librarythat expresses human antibodies, as described, for example, in Vaughanet al., Nat. Biotech. 14:309-314 (1996), Sheets et al., PNAS95:6157-6162 (1998), Hoogenboom and Winter, J. Mol. Biol. 227:381(1991), and Marks et al., J. Mol. Biol. 222:581 (1991). Techniques forthe generating and screening antibody phage libraries are also describedin U.S. Pat. Nos. 5,969,108; 6,172,197; 5,885,793; 6,521,404; 6,544,731;6,555,313; 6,582,915; 6,593,081; 6,300,064; 6,653,068; 6,706,484; and7,264,963; and Rothe et al., J. Mol. Biol. 376(4):1182-1200 (2008)(eachof which is herein incorporated by reference in its entirety).

Human anti-ALK7 antibodies can also be made in transgenic micecontaining human immunoglobulin loci that are capable upon immunizationof producing human antibodies in the absence of endogenousimmunoglobulin production. This approach is described for example, inU.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425;and 5,661,016.

Human anti-ALK7 antibodies can also be selected and/or isolated fromyeast-based antibody presentation libraries, as disclosed in, forexample, WO012/009568; WO09/036379; WO10/105256; WO03/074679 and U.S.Appl. Publ. No. US2002/0177170, the contents of each of which is hereinincorporated by reference in its entirety. Such libraries are designedin silico to be reflective of the diversity afforded by the humanpreimmune repertoire.

Alternatively, anti-ALK7 antibodies may be selected from ayeast-displayed antibody library see, for example: Blaise et al., Gene342(2):211-218 (2004); Boder et al., Nat Biotechnol. 15(6):553-557(1997); Kuroda et al., Biotechnol. Lett. 33(1):1-9 (2011). Review; Laueret al., J. Pharm. Sci. 101(1):102-15 (2012); Orcutt K. D. and Wittrup K.D. Antibody Engineering, yeast display and selection (2010), 207-233;Rakestraw et al., Protein Eng. Des. Sel. 24(6):525-30 (2011); and U.S.Pat. Nos. 6,423,538; 6,696,251; and 6,699,658.

Various techniques are known for the production of antigen-bindingantibody fragments. Traditionally, these fragments are derived viaproteolytic digestion of intact antibodies (see, e.g., Morimoto et al.,J. Biochem. Biophys. Meth. 24:107-117 (1993); and Brennan et al.,Science 229:81 (1985)). In certain embodiments an ALK7-binding antibodyfragments produced recombinantly. Fab, Fv, and scFv antibody fragmentscan all be expressed in and secreted from E. coli or other host cells,thus allowing the production of large amounts of these fragments. Suchan ALK7-binding antibody fragments can additionally be isolated from theantibody phage libraries discussed above. In some embodiments, theALK7-binding antibody fragment is a linear antibody as described in U.S.Pat. No. 5,641,870. Other techniques for the production ofantigen-binding antibody fragments are known in the art.

Known techniques can be readily adapted for the production ofsingle-chain antibodies that bind ALK7 (see, e.g., U.S. Pat. No.4,946,778). In addition, known methods can routinely be adapted for theconstruction of Fab expression libraries (see, e.g., Huse et al.,Science 246:1275-1281 (1989)) to allow rapid and effectiveidentification of monoclonal Fab fragments with the desired specificityfor ALK7. ALK7-binding antibody fragments can be produced by techniquesknown in the art including, but not limited to: (a) a F(ab′)2 fragmentproduced by pepsin digestion of an antibody; (b) a Fab fragmentgenerated by reducing the disulfide bridges of an F(ab′)2 fragment, (c)a Fab fragment generated by the treatment of the anti-ALK7 antibody withpapain and a reducing agent, and (d) Fv fragments.

In certain embodiments, an ALK7-binding protein (e.g., an anti-ALK7antibody) can be modified in order to increase its serum half-life. Thiscan be achieved, for example, by incorporation of a salvage receptorbinding epitope into the ALK7-binding protein by mutation of anappropriate region in the ALK7-binding protein or by incorporating thesalvage receptor epitope into a peptide tag that is then fused to theALK7-binding protein at either end or in the middle (e.g., by DNA orpeptide synthesis). Other methods to increase the serum half-life of anALK7-binding protein, e.g., conjugation to a heterologous molecule suchas PEG are known in the art.

Heteroconjugate ALK7-binding proteins (e.g., anti-ALK7 antibodies, suchas a full-length anti-ALK7 antibodies and ALK7-binding antibodyfragments, and variants and derivatives thereof) are also within thescope of the disclosure. Heteroconjugate ALK7-binding proteins arecomposed of two covalently joined proteins. It is contemplated that theheteroconjugate ALK7-binding proteins can be prepared in vitro usingknown methods in synthetic protein chemistry, including those involvingcrosslinking agents. For example, immunotoxins can be constructed usinga disulfide exchange reaction or by forming a thioether bond. Examplesof suitable reagents for this purpose include iminothiolate andmethyl-4-mercaptobutyrimidate.

ALK7-binding proteins can comprise any type of variable region thatprovides for the association of the antibody with ALK7. Such variableregion can comprise or be derived from any mammal that can be induced tomount a humoral response and generate immunoglobulins against the ALK7antigen. The variable region of an anti-ALK7 antibody can be, forexample, of human, murine, non-human primate (e.g., cynomolgus monkeys,macaques, etc.) or lupine origin. In some embodiments both the variableand constant regions of the modified anti-ALK7 antibodies are human. Inother embodiments the variable regions of compatible antibodies (usuallyderived from a non-human source) can be engineered or specificallytailored to improve the binding properties or reduce the immunogenicityof the molecule. In this respect, variable regions useful according tothe disclosure can be humanized or otherwise altered through theinclusion of imported amino acid sequences using affinity maturation,mutagenesis procedures, chain shuffling strategies and/or other methodsdescribed herein or otherwise know in the art.

In certain embodiments, the variable domains in both the heavy and lightchains of an anti-ALK7 antibody are altered by at least partialreplacement of one or more CDRs and/or by partial framework regionreplacement and sequence changing. Although the CDRs can be derived froman antibody of the same class or even subclass as the antibody fromwhich the framework regions are derived, it is envisaged that the CDRswill be derived from an antibody of different class and in certainembodiments from an antibody from a different species. It is notnecessary to replace all of the CDRs with the complete CDRs from thedonor variable region to transfer the antigen-binding capacity of onevariable domain to another. Rather, it is only necessary to transferthose residues that are necessary to maintain the activity of theantigen-binding site. It is well within the competence of those ofordinary skill in the art, to routinely obtain a functional antibodywith reduced immunogenicity. See, e.g., U.S. Pat. Nos. 5,585,089,5,693,761 and 5,693,762.

Alterations to the variable region notwithstanding, those of ordinaryskill in the art will appreciate that the modified anti-ALK7 antibody ofthe disclosure will comprise antibodies in which at least a fraction ofone or more of the constant region domains has been deleted or otherwisealtered so as to provide desired biochemical characteristics such asdecreased ADCC or increased serum half-life when compared with anantibody of approximately the same immunogenicity comprising a native orunaltered constant region. In some embodiments, the constant region ofthe modified anti-ALK7 antibodies comprise a human constant region.Modifications to the constant region can include additions, deletions orsubstitutions of one or more amino acids in one or more domains. Themodified anti-ALK7 antibodies disclosed herein can comprise alterationsor modifications to one or more of the three heavy chain constantdomains (CH1, CH2 or CH3) and/or to the light chain constant domain(CL). In some embodiments, the modified anti-ALK7 antibodies compriseconstant regions wherein one or more domains are partially or entirelydeleted are contemplated. In some embodiments, the modified anti-ALK7antibodies comprise domain deleted constructs or variants wherein theentire CH2 domain has been removed (ΔCH2 constructs). In someembodiments, the omitted constant region domain can be replaced by ashort amino acid spacer (e.g., 10 residues) that provides some of themolecular flexibility typically imparted by the absent constant region.

It is generally understood that the constant region mediates severaleffector functions. For example, binding of the Cl component ofcomplement to antibodies activates the complement system. Activation ofcomplement is important in the opsonization and lysis of cell pathogens.The activation of complement also stimulates the inflammatory responseand can also be involved in autoimmune hypersensitivity. Further,antibodies bind to cells via the Fc region, with a Fc receptor site onthe antibody Fc region binding to a Fc receptor (FcR) on a cell. Thereare a number of Fc receptors that are specific for different classes ofantibody, including IgG (gamma receptors), IgE (eta receptors), IgA(alpha receptors) and IgM (mu receptors). Binding of antibody to Fcreceptors on cell surfaces triggers a number of important and diversebiological responses including engulfment and destruction ofantibody-coated particles, clearance of immune complexes, lysis ofantibody-coated target cells by killer cells (called antibody-dependentcell-mediated cytotoxicity, or ADCC), release of inflammatory mediators,placental transfer and control of immunoglobulin production.

In certain embodiments, an anti-ALK7 antibody has an altered effectorfunction that, in turn, affects the biological profile of theadministered anti-ALK7 antibody. For example, the deletion orinactivation (through point mutations or other means) of a constantregion domain can reduce Fc receptor binding of the circulating modifiedantibody. In other cases the constant region modifications, can moderatecomplement binding and thus reduce the serum half-life and nonspecificassociation of a conjugated cytotoxin. Yet other modifications of theconstant region can be used to eliminate disulfide linkages oroligosaccharide moieties that allow for enhanced localization due toincreased antigen specificity or antibody flexibility. Similarly,modifications to the constant region in accordance with this disclosurecan easily be made using biochemical or molecular engineering techniquesknown to those of ordinary skill in the art.

In some embodiments, an ALK7-binding protein provided herein is an ALK7antibody that does not have one or more effector functions. Forinstance, in some embodiments, the anti-ALK7 antibody has noantibody-dependent cellular cytoxicity (ADCC) activity and/or nocomplement-dependent cytoxicity (CDC) activity. In certain embodiments,the anti-ALK7 antibody does not bind to an Fc receptor and/or complementfactors. In certain embodiments, the anti-ALK7 antibody has no effectorfunction. Examples of Fc sequence engineering modifications that reduceor eliminate ADCC and/or CDC activity and Fc receptor and/or complementfactor binding are described herein or otherwise know in the art, as areassays and procedures for testing the same.

In some embodiments, an anti-ALK7 antibody is engineered to fuse the CH3domain directly to the hinge region of the respective modified antibody.In other constructs a peptide spacer is inserted between the hingeregion and the modified CH2 and/or CH3 domains. For example, compatibleconstructs can be expressed in which the CH2 domain has been deleted andthe remaining CH3 domain (modified or unmodified) is joined to the hingeregion with a 5-20 amino acid spacer. Such a spacer can be added, forinstance, to ensure that the regulatory elements of the constant domainremain free and accessible or that the hinge region remains flexible.Amino acid spacers can, in some cases, prove to be immunogenic andelicit an unwanted immune response against the construct. Accordingly,in certain embodiments, any spacer added to the construct can berelatively non-immunogenic, or even omitted altogether, so as tomaintain the desired biochemical qualities of the modified anti-ALK7antibody.

In additional embodiments anti-ALK7 antibodies are modified by thepartial deletion or substitution of a few or even a single amino acid ina constant region. For example, the mutation of a single amino acid inselected areas of the CH2 domain can be enough to substantially reduceFc binding and thereby. Similarly one or more constant region domainsthat control the effector function (e.g., complement Cl Q binding) canbe fully or partially deleted. Such partial deletions of the constantregions can improve selected characteristics of the anti-ALK7 antibody(e.g., serum half-life) while leaving other desirable functionsassociated with the corresponding constant region domain intact. In someembodiments the constant region of the anti-ALK7 antibody is modifiedthrough the mutation or substitution of one or more amino acids thatenhances the profile of the resulting construct. In this respect it ispossible to disrupt the activity provided by a conserved binding site(e.g., Fc binding) while substantially maintaining the configuration andimmunogenic profile of the modified anti-ALK7 antibody. The disclosurealso provides an anti-ALK7 antibody that contains the addition of one ormore amino acids to the constant region to enhance desirablecharacteristics such, as decreasing or increasing effector function orproviding attachments sites for one or more cytotoxin, labeling orcarbohydrate moieties. In such embodiments it can be desirable to insertor replicate specific sequences derived from selected constant regiondomains.

The disclosure also provides an ALK7-binding protein that is a variantto an ALK7-binding protein provided herein (e.g., murine, chimeric,humanized and human ALK7-binding proteins). In particular embodiments,the variant ALK7-binding protein has at least one characteristicselected from the group consisting of: (a) decreases the formation of acomplex containing ALK7, a type II receptor (e.g., ActRIIA or ActRIIB),and one or more TGF-beta superfamily ligands (e.g., activin B, activinAB, Nodal, GDF1, GDF3 and/or GDF8) on the surface of cells expressingALK7 and the ActRII receptor in the presence of the one or more TGF-betasuperfamily ligands; (b) competes with one or more type II receptors forbinding to ALK7; (c) competes with one or more TGF-beta superfamilyligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) forbinding to ALK7; (d) decreases the phosphorylation of ALK7 in cellsexpressing ALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in thepresence of one or more TGF-beta super family ligands (e.g., GDF1, GDF3,GDF8, activin B, activin AB, and/or Nodal); (e) decreases thephosphorylation of Smads (e.g., Smad2 and/or Smad3) in cells expressingALK7 and a type II receptor (e.g., ActRIIA and/or ActRIIB) in thepresence of one or more TGF-beta ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (f) binds to ALK7 with a K_(D) of≤1 nM and ≥1 pM (e.g., as determined by BIACORE® analysis), and (g)decreases the formation of a complex containing ALK7, a co-receptor(e.g., cripto and/or cryptic), and one or more TGF-beta superfamilyligands (e.g., Nodal). In some embodiments, the ALK7-binding protein isan ALK7 antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

The provided ALK7-binding proteins, such as anti-ALK7 antibodies, can bederivatized to contain additional chemical moieties known in the art forimproving for example, the solubility, biological half-life,bioavailability, and to otherwise improve the stability, formulationand/or therapeutic properties of the ALK7-binding protein. Anon-exhaustive overview for such moieties can be found for example, inRemington's Pharmaceutical Sciences, 20th ed., Mack Publishing Co.,Easton, Pa. (2000).

Nucleic Acids Encoding ALK7-Binding Proteins and their Expression

Nucleic acid molecules and combinations of nucleic acid molecules thatencode an ALK7-binding protein are also provided. In some embodiments,the nucleic acids molecules encode an anti-ALK7 antibody, such as afull-length anti-ALK7 antibody and an ALK7-binding antibody fragment. Infurther embodiments, the disclosure provides nucleic acid molecules thatencode a variant or derivative of a full-length anti-ALK7 antibody or anALK7-binding antibody fragment provided herein.

The nucleic acid molecules disclosed herein can be in the form of RNA orin the form of DNA. DNA includes cDNA, genomic DNA, and synthetic DNA;and can be double-stranded or single-stranded, and if single strandedcan be the coding strand/or non-coding (anti-sense) strand. In certainembodiments, the nucleic acid molecule is isolated. In additionalembodiments, a nucleic acid molecule is substantially pure. In someembodiments the nucleic acid is cDNA or is derived from cDNA. In someembodiments the nucleic acid is be recombinantly produced.

In some embodiments, the nucleic acid molecule comprises an ALK7-bindingprotein coding sequence operably linked to a control sequence thatcontrols the expression of the coding sequence in a host cell or invitro. In particular embodiments, the coding sequence is a cDNA. Thedisclosure also relates to vectors containing nucleic acid moleculescomprises an ALK7-binding protein coding sequence operably linked to acontrol sequence that controls the expression of the coding sequence ina host cell or in vitro.

In some embodiments, the nucleic acid molecule comprises a codingsequence for a mature ALK7-binding protein that is fused in the samereading frame to a heterologous polynucleotide sequence. In someembodiments, the heterologous polynucleotide sequence encodes a leaderpeptide sequence that facilitates the secretion of the expressed proteinfrom the host cell transformed with the ALK7-binding protein encodingnucleic acid molecule(s). A protein containing a leader sequence isreferred to as a preprotein and can have the leader sequence cleaved bythe host cell to form the mature form of the ALK7-binding protein. Suchleader peptide sequences and their use facilitating the secretion ofrecombinant proteins in host cells is generally known in the art. Inadditional embodiments, the heterologous polynucleotide sequence encodesadditional 5′ amino acid residues that can function for example, tofacilitate purification, add or improve protein stability and/ortherapeutic or diagnostic properties of the recombinantly expressedALK7-binding protein.

In some embodiments the disclosure provides isolated nucleic acids suchas an ALK7-binding protein encoding cDNA fragments, sufficient for useas a hybridization probe, PCR primer or sequencing primer.

In some embodiments, the nucleic acid molecules encode an ALK7-bindingprotein that has at least one characteristic selected from the groupconsisting of: (a) decreases the formation of a complex containing ALK7,a type II receptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competes with one or more type II receptors for binding toALK7; (c) competes with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreases the phosphorylation of ALK7 in cells expressing ALK7and a type II receptor (e.g., ActRIIA or ActRIIB) in the presence of oneor more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8, activinB, activin AB, and/or Nodal); (e) decreases the phosphorylation of Smads(e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a type IIreceptor (e.g., ActRIIA and/or ActRIIB) in the presence of one or moreTGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB, and/orNodal); (f) binds to ALK7 with a K_(D) of ≤1 nM and ≥1 pM (e.g., asdetermined by BIACORE® analysis), and (g) decreases the formation of acomplex containing ALK7, a co-receptor (e.g., cripto and/or cryptic),and one or more TGF-beta superfamily ligands (e.g., Nodal). In someembodiments, the encoded ALK7-binding protein is an ALK7 antagonist(e.g., a neutralizing anti-ALK7 antibody). In further embodiments, theencoded ALK-7 binding protein increases lipolysis in adipose cellsexpressing ALK7. In some embodiments, the encoded ALK7-binding proteinhas 2, 3, or 4 of the above characteristics. In some embodiments, theencoded ALK7-binding protein has at least 2, at least 3, or at least 4,of the above characteristics. In some embodiments, the encodedALK7-binding protein cross-blocks or competes for binding to ALK7 withan antibody having an ALK7-binding VH and VL pair disclosed herein. Inadditional embodiments, the encoded ALK7-binding protein binds to thesame epitope of ALK7 as an antibody disclosed herein. In someembodiments, the encoded ALK7-binding protein cross-blocks or competesfor binding to ALK7 with an ALK7 binding antibody having a VH and VLpair disclosed herein. In additional embodiments, the encodedALK7-binding protein binds to the same epitope of ALK7 as an antibodydisclosed herein. In further embodiments, the nucleic acid moleculesencode an ALK7-binding protein that specifically binds ALK7 andcomprises a VH and a VL.

In some embodiments, the disclosure provides vectors and sets of vectorscontaining nucleic acids and sets of nucleic acids encoding theALK7-binding proteins provided herein. Host cells transformed with thesenucleic acids, sets of nucleic acids, vectors, and sets of vectors arealso provided, as are methods of making an using the ALK7-bindingproteins.

In some embodiments, the disclosure provides a host cell comprising anucleic acid molecule or combination of nucleic acid molecules or avector as provided above, where the host cell can, in some instancesexpress an ALK7-binding protein (e.g., an anti-ALK7 antibody such as, afull-length ALK7-antibody and an ALK7-binding antibody fragment), thatspecifically binds to ALK7. In further embodiments, the disclosureprovides a host cell transformed with a nucleic acid molecule orcombination of nucleic acid molecules or a vector as provided above,where the host cell can, in some instances express an ALK7-bindingprotein that specifically binds to ALK7. Such host cells can be utilizedin a method of making an ALK7-binding protein as provided herein, wherethe method includes (a) culturing the host cell and (b) isolating theALK7-binding proteins expressed from the host cell.

The disclosure also provides a method for making an ALK7-binding proteincomprising culturing a host cell (e.g., a hybridoma or transformedmammalian host cell) capable of expressing the ALK7-binding proteinunder suitable conditions and optionally provides a method for isolatingthe ALK7-binding protein secreted from the host cell. And the disclosureadditionally provides the ALK7-binding protein isolated using thedisclosed methods.

In certain embodiments the polynucleotides comprise the codingsequence(s) for the mature ALK7-binding protein(s) (e.g., anALK7-antibody, such as a full-length antibody and an ALK7-bindingantibody fragment) fused in the same reading frame to a marker sequencethat allows, for example, for purification of the encoded polypeptide.For example, the marker sequence can be a hexa-histidine tag supplied bya pQE-9 vector to provide for purification of the mature polypeptidefused to the marker in the case of a bacterial host, or the markersequence can be a hemagglutinin (HA) tag derived from the influenzahemagglutinin protein when a mammalian host (e.g., COS-7 cells) is used.

Nucleic acid variants encoding an ALK7-binding protein such as, ananti-ALK7 antibody and an ALK7-binding antibody fragment, are alsoprovided. Nucleic acid variants can contain alterations in the codingregions, non-coding regions, or both. In some embodiments the nucleicacid variants contain alterations that produce silent substitutions,additions, or deletions, but do not alter the properties or activitiesof the encoded polypeptide. In some embodiments, the nucleic acidvariants are produced by silent substitutions due to the degeneracy ofthe genetic code. Nucleic acid variants can be produced for a variety ofreasons, e.g., to optimize codon expression for a particular host(change codons in the human mRNA to those preferred by a bacterial hostsuch as E. coli). Vectors and cells comprising the nucleic acidsdescribed herein are also provided.

In some embodiments a nucleic acid sequence encoding an ALK7-bindingprotein (e.g., an anti-ALK7 antibody such as a full-length antibody andan ALK7-binding antibody fragment) is constructed by chemical synthesisusing an oligonucleotide synthesizer. Such oligonucleotides can bedesigned based on the amino acid sequence of the desired polypeptide andcodon optimization based on the host cell preferences. Standard methodscan routinely be applied to synthesize an isolate polynucleotidesequences encoding ALK7-binding proteins.

Once assembled (by synthesis, site-directed mutagenesis or anothermethod), the nucleic acid sequences encoding ALK7-binding proteins canroutinely be operably linked to a control sequence appropriate forexpression of the ALK7-binding protein in a desired host. In someembodiments, the nucleic acid sequence(s) encoding an ALK7-bindingprotein is inserted into one or more expression vectors and operablylinked to a control sequence(s) appropriate for expression of theprotein in a desired host. In order to obtain high expression levels ofa transfected coding sequence in a host, the coding sequence can beoperably linked to or associated with transcriptional and translationalexpression control sequences that are functional in the chosenexpression host.

In certain embodiments, recombinant expression vectors are used toamplify and express DNA encoding an ALK7-binding protein, such as, ananti-ALK7 antibody or an ALK7-binding antibody fragment. Recombinantexpression vectors are replicable DNA constructs which have synthetic orcDNA-derived DNA fragments encoding a polypeptide chain of anALK7-binding protein operably linked to suitable transcriptional ortranslational regulatory elements derived from mammalian, microbial,viral or insect genes. A transcriptional unit generally comprises anassembly of (1) a genetic element or elements having a regulatory rolein gene expression, for example, transcriptional promoters or enhancers,(2) a structural or coding sequence which is transcribed into mRNA andtranslated into protein, and (3) appropriate transcription andtranslation initiation and termination sequences, as described in detailbelow. Such regulatory elements can include an operator sequence tocontrol transcription. The ability to replicate in a host, usuallyconferred by an origin of replication, and a selection gene tofacilitate recognition of transformants can additionally beincorporated. DNA regions are operably linked when they are functionallyrelated to each other. For example, DNA for a signal peptide (secretoryleader) is operably linked to DNA for a polypeptide if it is expressedas a precursor which participates in the secretion of the polypeptide; apromoter is operably linked to a coding sequence if it controls thetranscription of the sequence; or a ribosome binding site is operablylinked to a coding sequence if it is positioned so as to permittranslation. Structural elements intended for use in yeast expressionsystems include a leader sequence enabling extracellular secretion oftranslated protein by a host cell. Alternatively, where a recombinantprotein is expressed without a leader or transport sequence, the proteincan include an N-terminal methionine residue. This residue canoptionally be subsequently cleaved from the expressed recombinantprotein to provide a final protein. In certain embodiments, thedisclosure provides a composition, e.g., a pharmaceutical composition,comprising a nucleic acid or vector of as described above or elsewhereherein, optionally further comprising one or more carriers, diluents,excipients, or other additives.

Also provided is a host cell transformed with the nucleic acid moleculeor cDNA molecules and/or the vectors disclosed herein. The disclosurealso provides host cells transformed with the disclosed nucleic acidmolecule or molecules operably linked to a control sequence andoptionally inserted into a vector. In some embodiments, the host cell isa mammalian host cell. In further embodiments, the mammalian host cellis a NS0 murine myeloma cell, a PER.C6® human cell, or a Chinese hamsterovary (CHO) cell. In other embodiments, the host cell is a hybridoma.

In additional embodiments, the disclosure provides a method of making anALK7-binding protein (e.g., an anti-ALK7 antibody such as, a full-lengthALK7-antibody and an ALK7-binding antibody fragment, and variants andderivatives thereof) provided herein comprising culturing a transformedhost cell or a hybridoma disclosed herein under suitable conditions forproducing the ALK7-binding protein. The disclosure optionally providesisolating the ALK7-binding protein secreted from the host cell. Thedisclosure also optionally provides the ALK7-binding protein producedusing this method and pharmaceutical compositions comprising theALK7-binding protein and a pharmaceutically acceptable carrier.

The choice of expression control sequence and expression vector willdepend upon the choice of host. A wide variety of expression host/vectorcombinations can be employed. Useful expression vectors for eukaryotichosts, include, for example, vectors comprising expression controlsequences from SV40, bovine papilloma virus, adenovirus andcytomegalovirus. Useful expression vectors for bacterial hosts includeknown bacterial plasmids, such as plasmids from E. coli, including pCR1,pBR322, pMB9 and their derivatives, and also wider host range plasmids,such as M13 and filamentous single-stranded DNA phages.

Suitable host cells for expression of an ALK7-binding protein, includeprokaryotes, yeast, insect or higher eukaryotic cells under the controlof appropriate promoters. Prokaryotes include gram negative or grampositive organisms, for example E. coli or bacilli. Higher eukaryoticcells include established cell lines of mammalian origin as describedbelow. Cell-free translation systems could also be employed. Additionalinformation regarding methods of protein production, including antibodyproduction, can be found, e.g., in U.S. Appl. Publ. No. 2008/0187954,U.S. Pat. Nos. 6,413,746 and 6,660,501, and Intl. Appl. Publ. No.WO04/009823, each of which is herein incorporated by reference in itsentirety.

Various mammalian or insect cell culture systems can also beadvantageously employed to express recombinant ALK7-binding proteins(e.g., an anti-ALK7 antibody such as, a full-length ALK7-antibody and anALK7-binding antibody fragment, and variants and derivatives thereof).Expression of recombinant ALK7-binding proteins in mammalian cells canbe performed because such proteins are generally correctly folded,appropriately modified and completely functional. Examples of suitablemammalian host cell lines include HEK-293 and HEK-293T, the COS-7 linesof monkey kidney cells, described by Gluzman (Cell 23:175 (1981)), andother cell lines including, for example, L cells, C127, 3T3. Chinesehamster ovary (CHO), HeLa and BHK cell lines. Mammalian expressionvectors can comprise nontranscribed elements such as an origin ofreplication, a suitable promoter and enhancer linked to the gene to beexpressed, and other 5′ or 3′ flanking nontranscribed sequences, and 5′or 3′ nontranslated sequences, such as necessary ribosome binding sites,a polyadenylation site, splice donor and acceptor sites, andtranscriptional termination sequences. Baculovirus systems forproduction of heterologous proteinsin sect cells are reviewed by Luckowand Summers, BioTechnology 6:47 (1988).

ALK7-binding proteins produced by a transformed host cell or hybridomacan be purified according to any suitable method. Such standard methodsinclude chromatography (e.g., ion exchange, affinity and sizing columnchromatography), centrifugation, differential solubility, or by anyother standard technique for protein purification. Affinity tags such ashexahistidine, maltose binding domain, influenza coat sequence andglutathione-S-transferase can be attached to the protein to allow easypurification by passage over an appropriate affinity column.ALK7-binding proteins can also be physically characterized using suchtechniques as proteolysis, nuclear magnetic resonance and x-raycrystallography.

For example, supernatants from systems that secrete recombinantALK7-binding proteins into culture media can be first concentrated usinga commercially available protein concentration filter, for example, anAmicon or Millipore Pellicon ultrafiltration unit. Following theconcentration step, the concentrate can be applied to a suitablepurification matrix. Alternatively, an anion exchange resin can beemployed, for example, a matrix or substrate having pendantdiethylaminoethyl (DEAE) groups. The matrices can be acrylamide,agarose, dextran, cellulose or other types commonly employed in proteinpurification. Alternatively, a cation exchange step can be employed.Suitable cation exchangers include various insoluble matrices comprisingsulfopropyl or carboxymethyl groups. Finally, one or more reversed-phasehigh performance liquid chromatography (RP-HPLC) steps employinghydrophobic RP-HPLC media, e.g., silica gel having pendant methyl orother aliphatic groups, can be employed to further purify anALK7-binding protein. Some or all of the foregoing purification steps,in various combinations, can also routinely be employed to provide ahomogeneous recombinant ALK7-binding proteins.

A recombinant ALK7-binding protein (e.g., an anti-ALK7 antibody such as,a full-length ALK7-antibody and an ALK7-binding antibody fragment andvariants and derivatives thereof) produced in bacterial culture can beisolated, for example, by initial extraction from cell pellets, followedby one or more concentration, salting-out, aqueous ion exchange or sizeexclusion chromatography steps. High performance liquid chromatography(HPLC) can be employed for final purification steps. Microbial cellsemployed in expression of a recombinant protein can be disrupted by anyconvenient method, including freeze-thaw cycling, sonication, mechanicaldisruption, or use of cell lysing agents.

Methods known in the art for purifying target binding proteins such asfull-length antibodies and antigen-binding antibody fragments alsoinclude, for example, those described in U.S. Appl. Publ. Nos.2008/0312425, 2008/0177048, and 2009/0187005, each of which isincorporated herein by reference herein in its entirety.

In certain embodiments, the ALK7-binding protein is not an antibody. Avariety of methods are known for identifying and producing non-antibodypolypeptides that bind with high affinity to a protein target. See,e.g., Skerra, Curr. Opin. Biotechnol. 18:295-304 (2007), Hosse et al.,Protein Science 15:14-27 (2006), Gill et al., Curr. Opin. Biotechnol.17:653-658 (2006), Nygren, FEBS J. 275:2668-2676 (2008), and Skerra,FEBS J. 275:2677-2683 (2008), each of which is herein incorporated byreference in its entirety. In certain embodiments, phage displaytechnology is used to identify/produce the ALK7-binding protein. Incertain embodiments, the polypeptide comprises a protein scaffold of atype selected from the group consisting of protein A, a lipocalin, afibronectin domain (e.g., Fibronectin type III (Fn3)), an ankyrinconsensus repeat domain, and thioredoxin.

Methods of Use and Pharmaceutical Compositions

The provided ALK7-binding proteins (including antibodies,immunoconjugates, and polypeptides) are useful in a variety ofapplications including, but not limited to, diagnostic methods andmethods of treating and/or ameliorating various diseases and conditionswith an ALK7-binding protein (e.g., an anti-ALK7 antibody). Methods areprovided for the use of an ALK7-binding protein (e.g., an anti-ALK7antibody such as, a full-length antibody that specifically binds ALK7and an ALK7-binding antibody fragment, and variants and derivativesthereof) to treat subjects having a disease or condition associated withALK7 signaling, altered ALK7 expression, and/or can be ameliorated byreduced ALK7 signaling. In additional embodiments, the disclosureprovides a pharmaceutical composition containing an ALK7-binding proteinprovided herein and a pharmaceutically acceptable carrier. In someembodiments, the disclosure provides a pharmaceutical compositioncontaining an ALK7-binding protein provided herein and apharmaceutically acceptable carrier, for use as a medicament. Thedisclosure also provides the use of the pharmaceutical compositionsdisclosed herein for treating and/or ameliorating a disease or conditionassociated with ALK7 signaling, altered ALK7 expression, and/or that canbe ameliorated by reduced ALK7 signaling. In some embodiments, thedisease or condition treated using the pharmaceutical compositionprovided herein is obesity (e.g., abdominal obesity); overweight;insulin resistance; metabolic syndrome and other metabolic diseases orconditions; a lipid disorder such as, low HDL, levels, high LDL levels,hyperlipidemia, hypertriglyceridemia or dyslipidemia; lipoproteinaberrations; decreased triglycerides; inflammation (e.g., liverinflammation and/or inflammation of adipose tissue), fatty liverdisease; non-alcoholic fatty liver disease; hyperglycemia; impairedglucose tolerance (IGT); hyperinsulinemia; high cholesterol (e.g., highLDL levels and hypercholesterolemia); cardiovascular disease such as,heart disease including coronary heart disease, congestive heartfailure, stroke, peripheral vascular disease, atherosclerosis;arteriosclerosis, and hypertension; Syndrome X; vascular restenosis;neuropathy; retinopathy; neurodegenerative disease; endothelialdysfunction, respiratory dysfunction, renal disease (e.g., nephropathy);pancreatitis; polycystic ovarian syndrome; elevated uric acid levels;haemochromatosis (iron overload); acanthosis nigricans (dark patches onthe skin); or cancer such as, myeloma (e.g., multiple myeloma,plasmacytoma, localized myeloma, and extramedullary myeloma), ovarian,breast, endometrial, and colon cancer); or a anotherdisorders/conditions associated with one or more of the above diseasesor conditions. In some embodiments, the disease or condition treatedusing the pharmaceutical composition provided herein is associated withoverweight (e.g., BMI of ≥25 kg/m²), or with too much body fat.

In some embodiments, a pharmaceutical composition contains anALK7-binding protein (e.g., an anti-ALK antagonist antibody) and apharmaceutically acceptable carrier, and the ALK7 binding proteinfurther comprises a labeling group or an effector group. A “label”refers to one or more elements, isotopes, or chemical compounds attachedto enable the detection in a screen. Labels generally fall into threeclasses: (a) isotopic labels, which may be radioactive or heavyisotopes, (b) small molecule labels, which may include fluorescent andcolorimetric dyes, or molecules such as biotin that enable otherlabeling methods, and (c) immune labels, which may be an epitopeincorporated as a fusion partner that is recognized by an antibody,“Labeling group” refers to any detectable label. In some embodiments,the labeling group is coupled to the ALK7-binding protein via a spacer(e.g., a peptide spacer) to reduce potential steric hindrance. Labelsmay be incorporated into the compound at any position and may beincorporated in vitro or in vivo during protein expression. Variousmethods for labeling proteins are known in the art and may be used inperforming the provided methods. In additional embodiments, the labelinggroup is selected from the group consisting of: isotopic labels,magnetic labels, redox active moieties, optical dyes, biotinylatedgroups and polypeptide epitopes recognized by a secondary reporter. Insome embodiments, the labeling group is a fluorescent protein such as aGreen Fluorescent Protein or derivative thereof (e.g., enhanced GFP,blue fluorescent protein or derivative thereof (e.g., EBFP (EnhancedBlue Fluorescent Protein), EBFP2, Azurite, mKalamal, cyan fluorescentprotein or derivative thereof (e.g., ECFP (Enhanced Cyan FluorescentProtein), Cerulean, CyPet), yellow fluorescent protein or derivativethereof (e.g., YFP, Citrine, Venus, YPet). In some embodiments, thepolypeptide epitope is a member selected from a biotin signalingpeptide, histidine peptide (his), hemagglutinin (HA), Flag, gold bindingpeptide. In additional embodiments the effector group is selected fromthe group consisting of a radioisotope, radionucleotide, a toxin, atherapeutic and a chemotherapeutic agent.

The ALK7-binding proteins of the present disclosure have applications inin vitro and in vivo diagnostic and therapeutic utilities. For example,the ALK7-binding proteins can be administered to cells in culture, e.g.,in vitro or in vivo, or in a subject, to treat, prevent or diagnose avariety of diseases or conditions. In some embodiments, the ALK7-bindingproteins are human antibodies, murine antibodies, or humanizedantibodies.

Also provided are methods of blocking ALK7 activity. In someembodiments, the method comprises contacting ALK7 with an antagonistALK7-binding protein. In further embodiments, the antagonistALK7-binding protein is an anti-ALK7 antibody. In some instances themethod is performed in vivo. In other instances, the method is performedin vitro. In some embodiments the blocked ALK7 activity is selected from(a) decreasing the formation of a complex containing ALK7, a type IIreceptor (e.g., ActRIIA or ActRIIB), and one or more TGF-betasuperfamily ligands (e.g., activin B, activin AB, Nodal, GDF1, GDF3and/or GDF8) on the surface of cells expressing ALK7 and the ActRIIreceptor in the presence of the one or more TGF-beta superfamilyligands; (b) competing with one or more type II receptors for binding toALK7; (c) competing with one or more TGF-beta superfamily ligands (e.g.,activin B, activin AB, Nodal, GDF1, GDF3 and/or GDF8) for binding toALK7; (d) decreasing the phosphorylation of ALK7 in cells expressingALK7 and a type II receptor (e.g., ActRIIA or ActRIIB) in the presenceof one or more TGF-beta super family ligands (e.g., GDF1, GDF3, GDF8,activin B, activin AB, and/or Nodal); (e) decreasing the phosphorylationof Smads (e.g., Smad2 and/or Smad3) in cells expressing ALK7 and a typeII receptor (e.g., ActRIIA and/or ActRIIB) in the presence of one ormore TGF-beta ligands (e.g., GDF1, GDF3, GDF8, activin B, activin AB,and/or Nodal); (f) binding to ALK7 with a K_(D) of ≤1 nM and ≥1 pM(e.g., as determined by BIACORE® analysis), and (g) decreasing theformation of a complex containing ALK7, a co-receptor (e.g., criptoand/or cryptic), and one or more TGF-beta superfamily ligands (e.g.,Nodal). In some embodiments, the ALK7-binding protein is an ALK7antagonist (e.g., a neutralizing anti-ALK7 antibody). In furtherembodiments, the ALK-7 binding protein increases lipolysis by 5% to100%, 10% to 80%, or 10% to 60%. In some embodiments, the ALK7-bindingprotein increase lipolysis in adipocyte cells by 5% to 100%, 10% to 80%,or 10% to 60%. In some embodiments, the ALK7-binding protein increaselipolysis in a lipolysis assay using adipocyte cells (e.g., whiteadipocytes) by 5% to 100%, 10% to 80%, or 10% to 60%. In furtherembodiments the lipolysis assay is performed in the presence of one ormore ALK7 ligands selected from the group consisting of: GDF1, GDF3,GDF8, activin B, activin A/B, and Nodal. In some embodiments, theALK7-binding protein has 2, 3, or 4 of the above characteristics. Insome embodiments, the ALK7-binding protein has at least 2, at least 3,or at least 4, of the above characteristics.

In one embodiment, the disclosure provides for the treatment, preventionand/or amelioration of a disease or condition that comprisesadministering an ALK7-binding protein (e.g., an anti-ALK antagonistantibody) to a subject that has a disease or condition, or is at risk ofdeveloping a disease or condition, associated with ALK7 signaling,altered ALK7 expression, and/or can be ameliorated by reduced ALK7signaling. In another embodiment the treatment includes theadministration of an ALK7-binding protein to an isolated tissue or cellsfrom a subject, where the subject has a disease or condition, or is atrisk of developing a disease or condition, associated with ALK7expression or ALK7 signaling.

The disclosure provides pharmaceutical compositions comprising anALK7-binding protein and a pharmaceutically acceptable carrier. Alsoprovided are methods for treating and/or ameliorating conditionsassociated with an ALK7-mediated activity in a subject, comprisingadministering to a subject in need thereof an effective amount of apharmaceutical composition comprising an ALK7-binding protein providedherein. In some embodiments, the ALK7-binding protein is administeredalone. In other embodiments, the ALK7-binding protein is administered asa combination therapy. Also provided are methods of reducing ALK7activity in a subject comprising administering an effective amount of anALK7-binding protein to a subject in need thereof.

As provided herein, an effective amount of an ALK7-binding protein(e.g., an antagonist anti-ALK7 antibody that specifically binds ALK7 oran antagonist ALK7-binding antibody fragment) can be administered forreducing body weight (e.g., promoting weight loss), reducing body weightgain (e.g., preventing weight gain), and/or treating obesity. In someembodiments, the ALK7-binding protein is an antibody disclosed herein.In some embodiments, the ALK7-binding protein is an ALK7 antagonistantibody. In some embodiments, the administered anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1A. In some embodiments, theadministered anti-ALK7-antibody binds to the same epitope of ALK7 as anantibody having a VH and a VL pair disclosed in Table 1A. In someembodiments, the administered anti-ALK7-antibody cross-blocks orcompetes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1B or Table 3. In some embodiments, the administeredanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1B or Table 3. In certaininstances, the subject has type 2 diabetes mellitus.

In one embodiment, the disclosure provides a method of reducing bodyweight comprising administering to a subject desiring to reduce bodyweight, or in need thereof, an effective amount of an ALK7-bindingprotein (e.g., an antagonist antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment). In some embodiments, theALK7-binding protein is an antibody disclosed herein. In someembodiments, the ALK7-binding protein is an ALK7 antagonist antibody. Insome embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1A. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1A. Insome embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1B or Table 3. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1B orTable 3. In some embodiments, the subject is overweight (e.g.,pre-obese). In some embodiments, the subject has a body mass index (BMI)of 25 kg/m² or greater. In further embodiments, the subject has a BMI of25 kg/m² to 29.9 kg/m², 30 kg/m² to 39.9 mkg/m², 25 kg/m² to 39.9 kg/m²,or 25 kg/m² to 50 kg/m². In some embodiments, the subject is obese. Insome embodiments, the subject has a BMI of 30 kg/m² or greater (e.g., 30to 39.9 kg/m² or 30 kg/m² to 50 kg/m²). In some embodiments, the subjectis morbidly obese. In some embodiments, the subject has a BMI of 40kg/m² or greater. In further embodiments, the subject has a BMI of 40kg/m² to 45 kg/m², or 40 kg/m² to 50 kg/m². In some embodiments, thesubject has central obesity (e.g., excess adiposity in the abdominalregion, including belly fat and/or visceral fat). In some embodiments,the subject has a waist/hip circumference ratio (WHR) of 0.85 orgreater. In some embodiments, the subject has peripheral obesity (e.g.,excess adiposity on the hips). In some embodiments, the subject has type2 diabetes mellitus. The ALK7-binding protein is administered alone oras a combination therapy. In some embodiments, the administration is anadjunct to diet and/or exercise.

In one embodiment, the disclosure provides a method of reducing weightgain comprising administering to a subject desiring to reduce weightgain, or in need thereof, an effective amount of an ALK7-binding protein(e.g., an antagonist antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment). In some embodiments, theALK7-binding protein is an antibody disclosed herein. In someembodiments, the ALK7-binding protein is an ALK7 antagonist antibody. Insome embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1A. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1A. Insome embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1B or Table 3. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1B orTable 3. In some embodiments, the subject is overweight (e.g.,pre-obese). In some embodiments, the subject has a BMI of 25 kg/m² orgreater. In further embodiments, the subject has a BMI of 25 kg/m² to29.9 kg/m², 30 kg/m² to 39.9 mkg/m², 25 kg/m² to 39.9 kg/m², or 25 kg/m²to 50 kg/m². In some embodiments, the subject is obese. In someembodiments, the subject has a BMI of 30 kg/m² or greater (e.g., 30 to39.9 kg/m² or 30 kg/m² to 50 kg/m²). In some embodiments, the subject ismorbidly obese. In some embodiments, the subject has a BMI of 40 kg/m²or greater. In further embodiments, the subject has a BMI of 40 kg/m² to45 kg/m², or 40 kg/m² to 50 kg/m². In some embodiments, the subject hastype 2 diabetes mellitus.

Also provided is a method of treating or preventing a disease orcondition associated with excess body weight, comprising administeringto a subject in need of treatment or prevention, an effective amount ofan ALK7-binding protein (e.g., an antagonist antibody that specificallybinds ALK7 or an antagonist ALK7-binding antibody fragment). In someembodiments, the administered ALK7-binding protein (e.g., an antagonistantibody) binds to the same epitope of ALK7 as an antibody having a VHand a VL pair disclosed in Table 1A. In some embodiments, theadministered ALK7-binding protein binds to the same epitope of ALK7 asan antibody having a VH and a VL pair disclosed in Table 1B or Table 3.In one embodiment, the treated or prevented disease or condition isobesity. In one embodiment, the treated or prevented disease orcondition is insulin resistance. In one embodiment, the treated orprevented disease or condition is a member selected from the groupconsisting of: dyslipidemia, hyperlipidemia (total cholesterol level>240mg/dL), hypercholesterolemia (e.g., total cholesterol level of >200mg/dL, >220 mg/dL, >240 mg/dL, >250 mg/dL, or >275 mg/dL), low HDL serumlevel (e.g., <40 mg/dL, <45 mg/dL, or <50 mg/dL), high LDL serum level(e.g., ≥100 mg/dL, ≥130 mg/dL, ≥160 mg/dL, or ≥190 mg/dL), andhypertriglyceridemia (e.g., a fasting TG level of ≥150 mg/dL, ≥175mg/dL, ≥200 mg/dL, ≥300 mg/dL, ≥400 mg/dL, or ≥499 mg/dL). In certaininstances, the administration is an adjunct to diet and/or exercise.

In another embodiment the disclosure provides a method of reducing bodyweight in a subject who is overweight. The method includes administeringto an overweight subject an effective amount of an ALK7-binding protein(e.g., an antagonist antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment). In some embodiments, theadministered ALK7-binding protein (e.g., an antagonist antibody)cross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1A. In some embodiments, theadministered ALK7-binding protein (e.g., an antagonist antibody)cross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1A. In some embodiments, theadministered ALK7-binding protein (e.g., an antagonist antibody) bindsto the same epitope of ALK7 as an antibody having a VH and a VL pairdisclosed in Table 1A. In some embodiments, the administeredALK7-binding protein (e.g., an antagonist antibody) cross-blocks orcompetes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1B or Table 3. In some embodiments, the administeredALK7-binding protein (e.g., an antagonist antibody) cross-blocks orcompetes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1B or Table 3. In some embodiments, the administeredALK7-binding protein (e.g., an antagonist antibody) binds to the sameepitope of ALK7 as an antibody having a VH and a VL pair disclosed inTable 1B or Table 3. In some embodiments, the subject has a body massindex (BMI) of 25 kg/m² or greater. In further embodiments, the subjecthas a BMI of 25 kg/m² to 29.9 kg/m², 30 kg/m² to 39.9 mkg/m², 25 kg/m²to 39.9 kg/m², or 25 kg/m² to 50 kg/m², or 27 to 40 kg/m². In someembodiments, the subject is obese. In some embodiments, the subject hasa BMI of 30 kg/m² or greater (e.g., 30 to 39.9 kg/m² or 30 kg/m² to 50kg/m²). The ALK7-binding protein is administered alone or as acombination therapy. In some embodiments, the administration is anadjunct to diet and/or exercise.

In one embodiment the disclosure provides a method of reducing bodyweight in an obese subject. The method includes administering to thesubject an effective amount of an ALK7-binding protein (e.g., anantagonist antibody that specifically binds ALK7 or an antagonistALK7-binding antibody fragment). In some embodiments, the administeredALK7-binding protein (e.g., an antagonist antibody) cross-blocks orcompetes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1A. In some embodiments, the administeredALK7-binding protein (e.g., an antagonist antibody) binds to the sameepitope of ALK7 as an antibody having a VH and a VL pair disclosed inTable 1A. In some embodiments, the administered ALK7-binding protein(e.g., an antagonist antibody) cross-blocks or competes for binding ALK7with an antibody having a VH and a VL pair disclosed in Table 1B orTable 3. In some embodiments, the administered ALK7-binding protein(e.g., an antagonist antibody) binds to the same epitope of ALK7 as anantibody having a VH and a VL pair disclosed in Table 1B or Table 3. Insome embodiments, the subject has a BMI of 30 kg/m² or greater (e.g., 30to 39.9 kg/m² or 30 kg/m² to 50 kg/m². In some embodiments, the subjecthas a BMI of 40 kg/m² or greater. In some embodiments, the subject hascentral obesity (e.g., excess adiposity in the abdominal region,including belly fat and/or visceral fat). In some embodiments, thesubject has a waist/hip circumference ratio (WHR) of 0.85 or greater. Insome embodiments, the subject has peripheral obesity (e.g., excessadiposity on the hips). The ALK7-binding protein is administered aloneor as a combination therapy. In some embodiments, the administration isan adjunct to diet and/or exercise.

In another embodiment, the disclosure provides a method of treatingand/or ameliorating obesity or a disease or condition associated withobesity, comprising administering to an obese subject, an effectiveamount of an ALK7-binding protein (e.g., an antagonist antibody thatspecifically binds ALK7 or an antagonist ALK7-binding antibodyfragment). In some embodiments, the antagonist ALK7-binding protein isan antibody disclosed herein. In some embodiments, the ALK7-bindingprotein is an antibody disclosed herein. In some embodiments, theALK7-binding protein is an ALK7 antagonist antibody. In someembodiments, the administered antagonist anti-ALK7-antibody cross-blocksor competes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1A. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1A. In some embodiments,the administered antagonist anti-ALK7-antibody cross-blocks or competesfor binding ALK7 with an antibody having a VH and a VL pair disclosed inTable 1B or Table 3. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1B or Table 3. In someembodiments, the subject has a BMI of 30 kg/m² or greater. In furtherembodiments, the subject has a BMI of 30 to 39.9 kg/m² or 30 kg/m² to 50kg/m². In some embodiments, the subject is morbidly obese. In someembodiments, the subject has a body BMI of 40 kg/m² or greater. Infurther embodiments, the subject has a BMI of 40 kg/m² to 45 kg/m², or40 kg/m² to 50 kg/m² In some embodiments, the subject has type 2diabetes mellitus. In some embodiments, the subject has a BMI of 30kg/m² or greater (e.g., 30 to 39.9 kg/m²). In some embodiments, thesubject has a BMI of at least 40 kg/m². In some embodiments, the subjecthas central obesity (e.g., excess adiposity in the abdominal region,including belly fat and/or visceral fat). In some embodiments, thesubject has a waist/hip circumference ratio (WHR) of 0.85 or greater. Insome embodiments, the subject has peripheral obesity (e.g., excessadiposity on the hips). The ALK7-binding protein is administered aloneor as a combination therapy. In some embodiments, the administration isan adjunct to diet and/or exercise.

Also provided is a method of treating or preventing a disease orcondition associated with obesity, comprising administering to a subjectin need of treatment or prevention, an effective amount of anALK7-binding protein (e.g., an antagonist antibody that specificallybinds ALK7 or an antagonist ALK7-binding antibody fragment). In someembodiments, the administered ALK7-binding protein (e.g., an antagonistantibody) cross-blocks or competes for binding ALK7 with an antibodyhaving a VH and a VL pair disclosed in Table 1A. In some embodiments,the administered ALK7-binding protein (e.g., an antagonist antibody)binds to the same epitope of ALK7 as an antibody having a VH and a VLpair disclosed in Table 1A. In some embodiments, the administeredALK7-binding protein (e.g., an antagonist antibody) cross-blocks orcompetes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1B or Table 3. In some embodiments, the administeredALK7-binding protein (e.g., an antagonist antibody) binds to the sameepitope of ALK7 as an antibody having a VH and a VL pair disclosed inTable 1B or Table 3. In one embodiment, the treated or prevented diseaseor condition is a member selected from the group consisting of:dyslipidemia, hyperlipidemia (total cholesterol level>240 mg/dL),hypercholesterolemia (e.g., total cholesterol level of >200 mg/dL, >220mg/dL, >240 mg/dL, >250 mg/dL, or >275 mg/dL), low HDL serum level(e.g., <40 mg/dL, <45 mg/dL, or <50 mg/dL), high LDL serum level (e.g.,≥100 mg/dL, ≥130 mg/dL, ≥160 mg/dL, or ≥190 mg/dL), andhypertriglyceridemia (e.g., a fasting TG level of ≥150 mg/dL, ≥175mg/dL, ≥200 mg/dL, ≥300 mg/dL, ≥400 mg/dL, or ≥499 mg/dL). In oneembodiment, the treated or prevented disease or condition iscardiovascular disease. In an additional embodiment, the treated orprevented disease or condition is hypertension (high blood pressure),myocardial infarction, stroke, peripheral artery disease, vasoregulatoindysfunction, arteriosclerosis congestive heart failure, atherosclerosis,coronary heart disease, or microvascular disease. In one embodiment, thetreated or prevented disease or condition is inflammation. In anotherembodiment, the treated or prevented disease or condition is a memberselected from the group: retinopathy, bowel disease, ulcerative colitis,and asthma, inflammation (e.g., inflammation of the liver and/orinflammation of adipose tissue). In one embodiment, the treated orprevented disease or condition is liver disease. In one embodiment, thetreated or prevented liver disease or condition is NAFLD. In oneembodiment, the liver disease is fatty liver. In one embodiment, theliver disease is NASH. In another embodiment, the treated or preventeddisease or condition is a member selected from the group:steatohepatitis, steatosis, fibrosis, and/or cirrhosis. In oneembodiment, the treated or prevented disease or condition is a memberselected from the group consisting of: cataract, macular degeneration,obstructive sleep apnea, phlebitis, gout, osteoarthritis, gallbladderdisease, renal disease, pulmonary disease (e.g., asthma, hypoventilationsyndrome, or respiratory dysfunction), and/or cancer (e.g., ovarian,breast, endometrial, liver, kidney, and/or colon cancer, and/or cancermetastasis (e.g., lymphatic metastasis, bloodstream metastasis, and/ortumor growth and invasion). In one embodiment, the treated or preventeddisease or condition is infection. In one embodiment, the treated orprevented disease or condition is a slow healing or nonhealing wound. Incertain instances, the administration is an adjunct to diet and/orexercise.

In one embodiment, the disclosure provides a method of reducing liverfat comprising administering an effective amount of an ALK7-bindingprotein (e.g., an antagonist antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment) to a subject in need thereof.In some embodiments, the ALK7-binding protein is an antibody disclosedherein. In some embodiments, the ALK7-binding protein is an ALK7antagonist antibody. In some embodiments, the administered antagonistanti-ALK7-antibody cross-blocks or competes for binding ALK7 with anantibody having a VH and a VL pair disclosed in Table 1A. In someembodiments, the administered antagonist anti-ALK7-antibody binds to thesame epitope of ALK7 as an antibody having a VH and a VL pair disclosedin Table 1A. In some embodiments, the administered antagonistanti-ALK7-antibody cross-blocks or competes for binding ALK7 with anantibody having a VH and a VL pair disclosed in Table 1B or Table 3. Insome embodiments, the administered antagonist anti-ALK7-antibody bindsto the same epitope of ALK7 as an antibody having a VH and a VL pairdisclosed in Table 1B or Table 3. In some embodiments, the subject isoverweight (e.g., pre-obese). In some embodiments, the subject has abody mass index (BMI) of 25 kg/m² or greater. In further embodiments,the subject has a BMI of 25 kg/m² to 29.9 kg/m², 30 kg/m² to 39.9mkg/m², 25 kg/m² to 39.9 kg/m², or 25 kg/m² to 50 kg/m². In someembodiments, the subject is obese. In some embodiments, the subject hasa BMI of 30 kg/m² or greater (e.g., 30 to 39.9 kg/m² or 30 kg/m² to 50kg/m²). In some embodiments, the subject is morbidly obese. In someembodiments, the subject has a BMI of 40 kg/m² or greater. In furtherembodiments, the subject has a BMI of 40 kg/m² to 45 kg/m², or 40 kg/m²to 50 kg/m². In some embodiments, the subject has central obesity (e.g.,excess adiposity in the abdominal region, including belly fat and/orvisceral fat). In some embodiments, the subject has a waist/hipcircumference ratio (WHR) of 0.85 or greater. In some embodiments, thesubject has peripheral obesity (e.g., excess adiposity on the hips). Insome embodiments, the subject has type 2 diabetes mellitus. TheALK7-binding protein is administered alone or as a combination therapy.In some embodiments, the administration is an adjunct to diet and/orexercise.

In another embodiment, the disclosure provides a method of treating,ameliorating, and/or preventing type 2 diabetes mellitus or a disease orcondition associated with diabetes comprising administering to a subjecthaving type 2 diabetes mellitus, or at risk of developing type 2diabetes, an effective amount of an ALK7-binding protein (e.g., anantagonist antibody that specifically binds ALK7 or an antagonistALK7-binding antibody fragment). In some embodiments, the ALK7-bindingprotein is an antibody disclosed herein. In some embodiments, theALK7-binding protein is an ALK7 antagonist antibody. In someembodiments, the administered antagonist anti-ALK7-antibody cross-blocksor competes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1A. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1A. In some embodiments,the administered antagonist anti-ALK7-antibody cross-blocks or competesfor binding ALK7 with an antibody having a VH and a VL pair disclosed inTable 1B or Table 3. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1B or Table 3. In someembodiments, the subject has a body mass index BMI of 30 kg/m² orgreater (e.g., 30 to 39.9 kg/m²). In some embodiments, the subject has aBMI of at least 40 kg/m². In some embodiments, the subject has centralobesity (e.g., excess adiposity in the abdominal region, including bellyfat and/or visceral fat). In some embodiments, the subject has a WHR of0.85 or greater. In some embodiments, the subject has peripheral obesity(e.g., excess adiposity on the hips). The ALK7-binding protein isadministered alone or as a combination therapy. In some embodiments, theadministration is an adjunct to diet and/or exercise.

Also provided is a method of treating, ameliorating or preventing adisease or condition associated with diabetes, comprising administeringto a subject having diabetes, an effective amount of an ALK7-bindingprotein (e.g., an antagonist antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment). In some embodiments, theadministered ALK7-binding protein (e.g., an antagonist antibody)cross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1A. In some embodiments, theadministered ALK7-binding protein (e.g., an antagonist antibody) bindsto the same epitope of ALK7 as an antibody having a VH and a VL pairdisclosed in Table 1A. In some embodiments, the administeredALK7-binding protein (e.g., an antagonist antibody) cross-blocks orcompetes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1B or Table 3. In some embodiments, the administeredALK7-binding protein (e.g., an antagonist antibody) binds to the sameepitope of ALK7 as an antibody having a VH and a VL pair disclosed inTable 1B or Table 3. In one embodiment, the treated or prevented diseaseor condition is a member selected from the group consisting of:dyslipidemia, hyperlipidemia (total cholesterol level>240 mg/dL),hypercholesterolemia (e.g., total cholesterol level of >200 mg/dL, >220mg/dL, >240 mg/dL, >250 mg/dL, or >275 mg/dL), low HDL serum level(e.g., <40 mg/dL, <45 mg/dL, or <50 mg/dL), high LDL serum level (e.g.,≥ 100 mg/dL, ≥130 mg/dL, ≥160 mg/dL, or ≥190 mg/dL), andhypertriglyceridemia (e.g., a fasting TG level of ≥150 mg/dL, ≥175mg/dL, ≥200 mg/dL, ≥300 mg/dL, ≥400 mg/dL, or ≥499 mg/dL). In oneembodiment, the treated or prevented disease or condition iscardiovascular disease. In an additional embodiment, the treated orprevented disease or condition is hypertension (high blood pressure),myocardial infarction, stroke, peripheral artery disease, vasoregulatoindysfunction, or arteriosclerosis. In one embodiment, the treated orprevented disease or condition is inflammation (e.g., systemicinflammation, inflammation of the liver, and inflammation of adiposetissue). In another embodiment, the treated or prevented disease orcondition is a member selected from the group: atherosclerosis,retinopathy, bowel disease, ulcerative colitis, asthma, inflammation ofthe liver, and/or inflammation of adipose tissue). In one embodiment,the treated or prevented disease or condition is liver disease. Inanother embodiment, the treated or prevented disease or condition is amember selected from the group: fatty liver disease, Steatohepatitis,steatosis, and/or cirrhosis. In one embodiment, the treated or preventeddisease or condition is a member selected from the group consisting of:cataract, macular degeneration, obstructive sleep apnea, phlebitis,gout, osteoarthritis, gallbladder disease, high cholesterol, pulmonarydisease (e.g., asthma, and/or hypoventilation syndrome), neuropathy,retinopathy, vasculopathy microangiopathy, nephropathy, renal failure,and/or cancer (e.g., ovarian, breast, endometrial, liver, kidney,pancreatic, and/or colon cancer), and cancer metastasis (e.g., lymphaticmetastasis, bloodstream metastasis, and/or tumor growth and invasion).In one embodiment, the treated or prevented disease or condition isinfection or a nonhealing wound. In certain instances, theadministration is an adjunct to diet and/or exercise.

The disclosure also provides a method for improving the blood-lipidprofile in a subject, comprising administering to a subject in need ofsuch treatment an effective amount of an ALK7-binding protein (e.g., anantagonist (neutralizing) antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment). In some embodiments, theantagonist ALK7-binding protein is an antibody disclosed herein. In someembodiments, the ALK7-binding protein is an antibody disclosed herein.In some embodiments, the ALK7-binding protein is an ALK7 antagonistantibody. In some embodiments, the administered antagonistanti-ALK7-antibody cross-blocks or competes for binding ALK7 with anantibody having a VH and a VL pair disclosed in Table 1A. In someembodiments, the administered antagonist anti-ALK7-antibody binds to thesame epitope of ALK7 as an antibody having a VH and a VL pair disclosedin Table 1A. In some embodiments, the ALK7-binding protein is an ALK7antagonist antibody. In some embodiments, the administered antagonistanti-ALK7-antibody cross-blocks or competes for binding ALK7 with anantibody having a VH and a VL pair disclosed in Table 1B or Table 3. Insome embodiments, the administered antagonist anti-ALK7-antibody bindsto the same epitope of ALK7 as an antibody having a VH and a VL pairdisclosed in Table 1B or Table 3. In some embodiments, the disclosureprovides a method for reducing levels of LDL cholesterol or increasinglevels of HDL-cholesterol. In one embodiment, the subject hasdyslipidemia. In another embodiment, the subject has elevated serumlipids (e.g., cholesterol (hypercholesterolemia) and/or triglycerides(e.g., hypertriglyceridemia). In one embodiment the subject has anLDL-C≥100 mg/dL, ≥130 mg/dL, or ≥160 mg/dL). In one embodiment thesubject has a TG≥150 mg/dL, ≥160 mg/dL, ≥170 mg/dL). In one embodiment,the subject has elevated plasma insulin levels (hyperinsulinemia; e.g.,fasting insulin level of >20 ug/ml can exceed 100). In some embodiments,the subject has type II diabetes.

According to one embodiment, the disclosure provides a method oftreating or preventing a metabolic disease or disorder or a conditionassociated with a metabolic disease or disorder, comprisingadministering an ALK7-binding protein (e.g., an antagonist antibody thatspecifically binds ALK7 or an antagonist ALK7-binding antibody fragment)to a subject in need thereof. In one embodiment, the treated metabolicdisease, disorder, or condition is hyperglycemia (e.g., >130 mg/dL inthe fasting state or following glucose administration during an oralglucose tolerance test). In one embodiment, the treated metabolicdisease, disorder, or condition is a lipid metabolism disease, disorder,or condition. In one embodiment, the treated metabolic disease,disorder, or condition is dislipidemia. In a further embodiment, thelipid metabolism disease, disorder, or condition is a member selectedfrom: low HDL levels, high LDL levels, high triglyceride levels,hyperlipidemia, and a lipoprotein aberration. In one embodiment, thesubject to which the ALK-7 binding protein is administered has a totalcholesterol level of >200 mg/dL, >220 mg/dL, >240 mg/dL, >250 mg/dL,or >275 mg/dL. In one embodiment, the subject to which the ALK-7 bindingprotein is administered has a HDL serum level of <40 mg/dL, <45 mg/dL,or <50 mg/dL). In one embodiment, the subject to which the ALK-7 bindingprotein is administered has a LDL serum level≥100 mg/dL, ≥130 mg/dL,≥160 mg/dL, or ≥190 mg/dL. In one embodiment, the subject to which theALK-7 binding protein is administered has, fasting TG level of ≥150mg/dL, ≥175 mg/dL, ≥200 mg/dL, ≥300 mg/dL, ≥400 mg/dL, or ≥499 mg/dL. Inone embodiment, the treated metabolic disease, disorder, or condition isa glucose metabolism disease, disorder, or condition. In a furtherembodiment, the glucose metabolism disease, disorder, or condition is amember selected from: glucose intolerance, insulin resistance, impairedglucose tolerance (IGT), impaired fasting glucose (IFG). In oneembodiment, the treated metabolic disease, disorder, or condition is amember selected from the group consisting of: high uric acid levels,NAFLD, fatty liver, NASH, and polycystic ovarian syndrome. In oneembodiment, the treated subject has hyperinsulinemia. In one embodiment,the treated subject is obese (e.g., the subject has visceral orabdominal obesity). In another embodiment, the treated subject has typeII diabetes.

Metabolic syndrome is a condition involving a set of disorders thatenhances the risk of heart disease. The major components of metabolicsyndrome are excess weight, the cardiovascular parameters (high bloodpressure, dyslipidemia, high levels of triglycerides and/or low levelsof HDL in the blood), atherosclerosis, diabetes, and/or insulinresistance. A subject having several of these components, i.e. metabolicsyndrome, is highly prone to heart disease, though each component is arisk factor. The disclosure also provides a method for treating orpreventing 1, 2, 3, or more of the above components of metabolicsyndrome, comprising administering to a subject in need of treatment aneffective amount of an ALK7-binding protein (e.g., an antagonistantibody that specifically binds ALK7 or an antagonist ALK7-bindingantibody fragment).

Additionally provided is a method of treating, preventing orameliorating a cardiovascular disease or condition, comprisingadministering an ALK7-binding protein (e.g., an antagonist antibody thatspecifically binds ALK7 or an antagonist ALK7-binding antibody fragment)to a subject in need thereof. In one embodiment, the treated, prevented,or ameliorated cardiovascular disease or condition is atherosclerosis.In one embodiment, the treated, prevented, or ameliorated cardiovasculardisease or condition is hypertension (e.g., blood pressure>130/80 mmHgor >140/90 mmHg, in a resting state). In one embodiment, thecardiovascular disease or condition is peripheral vascular disease, amicrovascular or microvascular complication, stroke, and/or retinopathy.In one embodiment, the cardiovascular disease is atherosclerosis(coronary heart disease disease).

In one embodiment, the disclosure provides a method for treating and/orameliorating an inflammatory disease or condition that comprisesadministering an ALK7-binding protein (e.g., an antagonist antibody thatspecifically binds ALK7 or an antagonist ALK7-binding antibody fragment)to a subject in need thereof. In one embodiment, the inflammatorydisease or condition is chronic inflammation. In another embodiment, theinflammatory disease or condition is inflammation of adipose tissue. Inanother embodiment, the disease or condition is inflammation of theliver. In one embodiment, the disease or condition is NAFLD. In afurther embodiment, the disease or condition is fatty liver. In afurther embodiment, the disease or condition is steatosis (e.g.,nonalcoholic Steatohepatitis (NASH).

This disclosure also provides a method of improving glycemic control,comprising administering to a subject in need of treatment an effectiveamount of an ALK7-binding protein (e.g., an antagonist antibody thatspecifically binds ALK7 or an antagonist ALK7-binding antibodyfragment). In one embodiment, the subject to which the ALK7-bindingprotein is administered has a fasting blood sugar levelof >130, >135, >140, >145, or >150 mg/dL. In one embodiment, the subjectto which the ALK7-binding protein is administered has a postprandialblood sugar level of >180, >185, >190, >195, or >200 mg/dL 2 hours aftereating. In certain instances, the administration is an adjunct to dietand/or exercise. The administration can also reduce body weight or treatobesity. In certain instances, the subject has type 2 diabetes mellitus.In certain instances, the subject has a BMI of 27 to 40 kg/m2. Incertain instances, the subject has a BMI of 30 to 39.9 kg/m2. In certaininstances, the subject has a BMI of at least 40. In certain instances,the subject is overweight. In certain instances, the subject is obese.An improvement in glycemic control can be assessed using techniquesknown in the art such as a mixed-meal test.

The disclosure also provides compositions and methods for treating,preventing or ameliorating hyperglycemia or a condition associated withhyperglycemia in a subject comprising administering to a subject in needof such treatment an effective amount of an ALK7-binding protein (e.g.,an antagonist anti-ALK7 antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment). In one embodiment, thesubject to which the ALK7-binding protein is administered has a fastingblood sugar level of >130, >135, >140, >145, or >150 mg/dL. In oneembodiment, the subject to which the ALK7-binding protein isadministered has a postprandial blood sugar levelof >180, >185, >190, >195, or >200 mg/dL 2 hours after eating. In oneembodiment, the result of the treatment, prevention or amelioration is amember selected from the group consisting of: a decrease in serum levelsof glucose, a decrease in serum levels of triglycerides, a decrease inserum levels of insulin, and/or a decrease in serum levels ofnon-esterified fatty acids, as compared to serum levels in the subjectprior to treatment. In one embodiment, the result of the treatment,prevention or amelioration is an increase in body temperature of about0.4° C. to 1° C. as compared to body temperature of the subject prior totreatment. In some embodiments, the ALK7-binding protein is anantagonist anti-ALK7 protein. In some embodiments, the ALK7-bindingprotein is an antagonist anti-ALK7 antibody or an ALK7-binding fragmentthereof. In some embodiments, the ALK7-binding protein is an antagonistanti-ALK7 antibody or an ALK7-binding fragment thereof disclosed herein.In some embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1A. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1A. Insome embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1B or Table 3. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1B orTable 3. In some embodiments, the administration also reduces bodyweight of the subject.

In another embodiment, the disclosure provides a method of decreasingplasma insulin levels in a subject, comprising administering aneffective amount of an ALK7-binding protein (e.g., an antagonistanti-ALK7 antibody that specifically binds ALK7 or an antagonistALK7-binding antibody fragment) to a subject in need of such treatment.In one embodiment, the subject to which the ALK7-binding protein isadministered has a fasting blood sugar level of >130, >135, >140, >145,or >150 mg/dL. In one embodiment, the subject to which the ALK7-bindingprotein is administered has a postprandial blood sugar levelof >180, >185, >190, >195, or >200 mg/dL 2 hours after eating. In oneembodiment, the subject is overweight. In one embodiment, the subject isobese. In another embodiment, the subject has type 2 diabetes. In someembodiments, the ALK7-binding protein is an antagonist anti-ALK7protein. In some embodiments, the ALK7-binding protein is an antagonistanti-ALK7 antibody or an ALK7-binding fragment thereof. In someembodiments, the ALK7-binding protein is an antagonist anti-ALK7antibody or an ALK7-binding fragment thereof disclosed herein. In someembodiments, the administered antagonist anti-ALK7-antibody cross-blocksor competes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1A. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1A. In some embodiments,the administered antagonist anti-ALK7-antibody cross-blocks or competesfor binding ALK7 with an antibody having a VH and a VL pair disclosed inTable 1B or Table 3. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1B or Table 3.

The disclosure also provides compositions and methods for treating,preventing or ameliorating hyperglycemia or a condition associated withhyperglycemia in a subject comprising administering to a subject in needof such treatment an effective amount of an ALK7-binding protein (e.g.,an antagonist anti-ALK7 antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment). In one embodiment, thesubject to which the ALK7-binding protein is administered has a fastingblood sugar level of >130, >135, >140, >145, or >150 mg/dL. In oneembodiment, the subject to which the ALK7-binding protein isadministered has a postprandial blood sugar levelof >180, >185, >190, >195, or >200 mg/dL 2 hours after eating. In oneembodiment, the result of the treatment, prevention or amelioration is amember selected from the group consisting of: a decrease in serum levelsof glucose, a decrease in serum levels of triglycerides, a decrease inserum levels of insulin, and/or a decrease in serum levels ofnon-esterified fatty acids, as compared to serum levels in the subjectprior to treatment. In one embodiment, the result of the treatment,prevention or amelioration is an increase in body temperature of about0.4° C. to 1° C. as compared to body temperature of the subject prior totreatment. In some embodiments, the ALK7-binding protein is anantagonist anti-ALK7 protein. In some embodiments, the ALK7-bindingprotein is an antagonist anti-ALK7 antibody or an ALK7-binding fragmentthereof. In some embodiments, the ALK7-binding protein is an antagonistanti-ALK7 antibody or an ALK7-binding fragment thereof disclosed herein.In some embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1A. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1A. Insome embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1B or Table 3. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1B orTable 3 In some embodiments, the administration also reduces body weightof the subject.

In another embodiment, the disclosure provides a method of decreasingplasma insulin levels in a subject, comprising administering aneffective amount of an ALK7-binding protein (e.g., an antagonistanti-ALK7 antibody that specifically binds ALK7 or an antagonistALK7-binding antibody fragment) to a subject in need of such treatment.In one embodiment, the subject to which the ALK7-binding protein isadministered has a fasting blood sugar level of >130, >135, >140, >145,or >150 mg/dL. In one embodiment, the subject to which the ALK7-bindingprotein is administered has a postprandial blood sugar levelof >180, >185, >190, >195, or >200 mg/dL 2 hours after eating. In oneembodiment, the subject is overweight. In one embodiment, the subject isobese. In another embodiment, the subject has type 2 diabetes. In someembodiments, the ALK7-binding protein is an antagonist anti-ALK7protein. In some embodiments, the ALK7-binding protein is an antagonistanti-ALK7 antibody or an ALK7-binding fragment thereof. In someembodiments, the ALK7-binding protein is an antagonist anti-ALK7antibody or an ALK7-binding fragment thereof disclosed herein. In someembodiments, the administered antagonist anti-ALK7-antibody cross-blocksor competes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1A. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1A. In some embodiments,the administered antagonist anti-ALK7-antibody cross-blocks or competesfor binding ALK7 with an antibody having a VH and a VL pair disclosed inTable 1B or Table 3. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1B or Table 3.

In another embodiment, the disclosure provides a method of treating,preventing, or ameliorating liver disease in a subject, comprisingadministering an effective amount of an ALK7-binding protein (e.g., anantagonist anti-ALK7 antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment) to a subject having a liverdisease. In one embodiment, the subject has inflammation of the liver.In one embodiment, the subject has NAFLD. In on embodiment the subjecthas fatty liver. In another embodiment, the subject has NASH. In oneembodiment, the treated, prevented or ameliorated liver disease isfibrosis, scarring, cirrhosis, or liver failure. In another embodiment,the treated, prevented or ameliorated liver disease is liver cancer. Inone embodiment, the subject is overweight. In another embodiment, thesubject is obese. In another embodiment, the subject has type 2diabetes. In some embodiments, the ALK7-binding protein is an antagonistanti-ALK7 protein. In some embodiments, the ALK7-binding protein is anantagonist anti-ALK7 antibody or an ALK7-binding fragment thereof. Insome embodiments, the ALK7-binding protein is an antagonist anti-ALK7antibody or an ALK7-binding fragment thereof disclosed herein. In someembodiments, the administered antagonist anti-ALK7-antibody cross-blocksor competes for binding ALK7 with an antibody having a VH and a VL pairdisclosed in Table 1A. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1A. In some embodiments,the administered antagonist anti-ALK7-antibody cross-blocks or competesfor binding ALK7 with an antibody having a VH and a VL pair disclosed inTable 1B or Table 3. In some embodiments, the administered antagonistanti-ALK7-antibody binds to the same epitope of ALK7 as an antibodyhaving a VH and a VL pair disclosed in Table 1B or Table 3.

In additional embodiments, the disclosure provides methods of treatingand/or ameliorating cancer or a condition associated with cancer, thatcomprises administering an ALK7-binding protein (e.g., an anti-ALK7antibody or ALK7-binding fragment thereof) to a subject in need thereof.In some embodiments the ALK7-binding protein is an anti-ALK7 antibody oran ALK7-binding fragment thereof. In some embodiments, the subject has acancer selected from the group consisting of a myeloma (e.g., multiplemyeloma, plasmacytoma, localized myeloma, or extramedullary myeloma), oran ovarian, breast, colon, endometrial, liver, kidney, pancreatic,gastric, uterine or colon cancer. In some embodiments, ALK7-bindingprotein is administered to treat or prevent lymphatic metastasis,bloodstream metastasis, tumor growth, or tumor invasion.

In one embodiment, the disclosure provides a method of treating cancerthat comprises contacting a cancer cell, tumor associated-stromal cell,or endothelial cell expressing ALK7 with an ALK7-binding protein (e.g.,an antagonist anti-ALK7 antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment). In additional embodimentsthe cancer cell is a myeloma (e.g., multiple myeloma, plasmacytoma,localized myeloma, or extramedullary myeloma), ovarian, breast, colon,endometrial, liver, kidney, pancreatic, gastric, uterine and/or coloncancer cell. In some embodiments the contacted cell is from a cancerline. In some embodiments the cancer cell is contacted in vivo.

In one embodiment, the disclosure provides a method of for increasinglipolysis comprising contacting a white adipocyte or adipose tissue withan antagonist ALK7-binding protein (e.g., an antagonist anti-ALK7antibody that specifically binds ALK7 or an antagonist ALK7-bindingantibody fragment). In some embodiments, the ALK-7 binding proteinincreases lipolysis by 5% to 100%, 10% to 80%, or 10% to 60%. In someembodiments, the ALK7-binding protein increase lipolysis in adiposecells by 5% to 100%, 10% to 80%, or 10% to 60%. In some embodiments, theALK7-binding protein increase lipolysis in a lipolysis assay by 5% to100%, 10% to 80%, or 10% to 60%. In further embodiments the lipolysisassay is performed in the presence of one or more ALK7 ligands selectedfrom the group consisting of: GDF1, GDF3, GDF8, activin B, activin A/B,and Nodal. In some embodiments, the antagonist ALK7 binding protein isan antibody. In some embodiments, the antagonist anti-ALK7-antibodycomprises an antibody provided herein. In some embodiments theantagonist antibody cross-blocks or competes for binding ALK7 with anantibody having a VH and a VL pair disclosed in Table 1A. In someembodiments, the antagonist anti-ALK7-antibody binds to the same epitopeof ALK7 as an antibody having a VH and a VL pair disclosed in Table 1A.In some embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1B or Table 3. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1B orTable 3. In some embodiments the white adipose cell or adipose tissue iscontacted in vitro. In some embodiments the differentiated white adiposecell or adipose tissue is contacted in vivo. In one embodiment, themethod is carried out in vivo, for example, in a mammalian subject(e.g., an animal model). In a further embodiment, the subject is ahuman. In some embodiments, the method leads to increased glycerolproduction. In further embodiments, the method leads to increasedglycerol and/or free fatty acid in an adipocyte culture. In someembodiments, the method leads to decreased triglyceride (TG) content inthe adipose cell or tissue. In some embodiments, the method leads to adecreased plasma TG level in a subject.

In another embodiment, the disclosure provides a method of increasingadrenergic receptor-β (ADRB) signaling in an adipose cell or tissue. Themethod comprises contacting a differentiated white adipocyte or adiposetissue with an antagonist ALK7-binding protein (e.g., an antagonistanti-ALK7 antibody that specifically binds ALK7 or an antagonistALK7-binding antibody fragment) in an amount sufficient to increase ADRBsignaling. In some embodiments, the antagonist ALK7 binding protein isan antibody. In some embodiments, the antagonist anti-ALK7-antibodycomprises an antibody provided herein. In some embodiments theantagonist antibody cross-blocks or competes for binding ALK7 with anantibody having a VH and a VL pair disclosed in Table 1A. In someembodiments, the antagonist anti-ALK7-antibody binds to the same epitopeof ALK7 as an antibody having a VH and a VL pair disclosed in Table 1A.In some embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1B or Table 3. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1B orTable 3. In some embodiments the differentiated white adipocyte oradipose tissue is contacted in vitro. In some embodiments thedifferentiated white adipocyte or adipose tissue is contacted in vivo.In one embodiment, the method is carried out in vivo, for example, in amammalian subject (e.g., an animal model). In a further embodiment, thesubject is a human. In some embodiments, the method leads to increasedglycerol production. In further embodiments, the method leads toincreased glycerol and/or free fatty acid in an adipocyte culture. Insome embodiments, the method leads to decreased TG content in theadipose cell or tissue. In some embodiments, the method leads to adecreased plasma TG level in a subject. In some embodiments, the methodleads to an increased ADRB signaling in an adipocyte or adipose tissueduring nutrient overload.

In another embodiment, the disclosure provides a method of decreasingperoxisome proliferator-activated receptor-gamma (PPAR gamma) signalingin an adipose cell or adipose tissue (e.g., differentiated whiteadipocytes). The method includes contacting a differentiated whiteadipocyte or adipose tissue with an antagonist ALK7-binding protein(e.g., an antagonist anti-ALK7 antibody that specifically binds ALK7 oran antagonist ALK7-binding antibody fragment) in an amount effective todecrease PPAR gamma activity. In some embodiments, the antagonist ALK7binding protein is an antibody. In some embodiments, the antagonistanti-ALK7-antibody comprises an antibody provided herein. In someembodiments the antagonist antibody cross-blocks or competes for bindingALK7 with an antibody having a VH and a VL pair disclosed in Table 1A.In some embodiments, the antagonist anti-ALK7-antibody binds to the sameepitope of ALK7 as an antibody having a VH and a VL pair disclosed inTable 1A. In some embodiments, the administered antagonistanti-ALK7-antibody cross-blocks or competes for binding ALK7 with anantibody having a VH and a VL pair disclosed in Table 1B or Table 3. Insome embodiments, the administered antagonist anti-ALK7-antibody bindsto the same epitope of ALK7 as an antibody having a VH and a VL pairdisclosed in Table 1B or Table 3. In some embodiments the differentiatedwhite adipocyte or adipose tissue is contacted in vitro. In someembodiments the differentiated white adipocyte or adipose tissue iscontacted in vivo. In one embodiment, the method is carried out in vivo,for example, in a mammalian subject (e.g., an animal model). In afurther embodiment, the subject is a human. In some embodiments, themethod leads to increased glycerol production. In further embodiments,the method leads to increased glycerol and/or free fatty acid in anadipocyte culture. In some embodiments, the method leads to decreased TGcontent in the adipose cell or tissue. In some embodiments, the methodleads to a decreased plasma TG level in a subject.

In another embodiment, the disclosure provides a method of decreasinginsulin resistance in an adipose cell or adipose tissue (e.g.,differentiated white adipocytes). The method includes contacting anadipocyte or adipose tissue with an antagonist ALK7-binding protein(e.g., an antagonist anti-ALK7 antibody that specifically binds ALK7 oran antagonist ALK7-binding antibody fragment) in an amount effective toreduce insulin resistance. In some embodiments, the antagonist ALK7binding protein is an antibody. In some embodiments, the antagonistanti-ALK7-antibody comprises an antibody provided herein. In someembodiments the antagonist antibody cross-blocks or competes for bindingALK7 with an antibody having a VH and a VL pair disclosed in Table 1A.In some embodiments, the antagonist anti-ALK7-antibody binds to the sameepitope of ALK7 as an antibody having a VH and a VL pair disclosed inTable 1A. In some embodiments, the administered antagonistanti-ALK7-antibody cross-blocks or competes for binding ALK7 with anantibody having a VH and a VL pair disclosed in Table 1B or Table 3. Insome embodiments, the administered antagonist anti-ALK7-antibody bindsto the same epitope of ALK7 as an antibody having a VH and a VL pairdisclosed in Table 1B or Table 3. In some embodiments the differentiatedwhite adipocyte or adipose tissue is contacted in vitro. In someembodiments the differentiated white adipocyte or adipose tissue iscontacted in vivo. In one embodiment, the method is carried out in vivo,for example, in a mammalian subject (e.g., an animal model). In afurther embodiment, the subject is a human.

In another embodiment, the disclosure provides a method of increasingthe metabolic rate of an adipose cell or tissue. The method includescontacting an adipocyte or adipose tissue with an antagonistALK7-binding protein (e.g., an antagonist anti-ALK7 antibody thatspecifically binds ALK7 or an antagonist ALK7-binding antibody fragment)in an amount effective to increase metabolism of the adipocyte ortissue. In some embodiments, the antagonist ALK7 binding protein is anantibody. In some embodiments, the antagonist anti-ALK7-antibodycomprises an antibody provided herein. In some embodiments theantagonist antibody cross-blocks or competes for binding ALK7 with anantibody having a VH and a VL pair disclosed in Table 1A. In someembodiments, the antagonist anti-ALK7-antibody binds to the same epitopeof ALK7 as an antibody having a VH and a VL pair disclosed in Table 1A.In some embodiments, the administered antagonist anti-ALK7-antibodycross-blocks or competes for binding ALK7 with an antibody having a VHand a VL pair disclosed in Table 1B or Table 3. In some embodiments, theadministered antagonist anti-ALK7-antibody binds to the same epitope ofALK7 as an antibody having a VH and a VL pair disclosed in Table 1B orTable 3. In some embodiments the differentiated white adipocyte oradipose tissue is contacted in vitro. In some embodiments thedifferentiated white adipocyte or adipose tissue is contacted in vivo.In one embodiment, the method is carried out in vivo, for example, in amammalian subject (e.g., an animal model). In a further embodiment, thesubject is a human.

The disclosure provides methods that comprise administering atherapeutically effective amount of a ALK7-binding protein (e.g., anantagonist anti-ALK7 antibody that specifically binds ALK7 or anantagonist ALK7-binding antibody fragment), alone or in combination withone or more additional therapies (e.g., one or more additionaltherapeutic agents) to a subject having, or at risk for developing, anALK7-mediated disease and/or condition such as, obesity (e.g., abdominalor visceral obesity); overweight; insulin resistance; metabolic syndromeand other metabolic diseases or conditions; a lipid disorder such as,low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia ordyslipidemia; lipoprotein aberrations; decreased triglycerides;inflammation (e.g., liver inflammation and/or inflammation of adiposetissue), fatty liver disease; non-alcoholic fatty liver disease;hyperglycemia; impaired glucose tolerance (IGT); hyperinsulinemia; highcholesterol (e.g., high LDL levels and/or hypercholesterolemia);cardiovascular disease such as, heart disease including coronary heartdisease, congestive heart failure, stroke, peripheral vascular disease,atherosclerosis; arteriosclerosis, and/or hypertension; Syndrome X;vascular restenosis; neuropathy; retinopathy; neurodegenerative disease;endothelial dysfunction, respiratory dysfunction, renal disease (e.g.,nephropathy); pancreatitis; polycystic ovarian syndrome; elevated uricacid levels; haemochromatosis (iron overload); acanthosis nigricans(dark patches on the skin); and/or cancer (e.g., myeloma (e.g., multiplemyeloma, plasmacytoma, localized myeloma, or extramedullary myeloma),ovarian, breast, colon, endometrial, liver, kidney, pancreatic, gastric,uterine or colon cancer r); and/or other disorders/conditions associatedwith one or more of the above diseases or conditions, and/or withoverweight (e.g., BMI of ≥25 kg/m²), or with too much body fat.

Also provided is the use of an ALK7-binding protein provided herein fordiagnostic monitoring of protein levels (e.g., ALK7 levels) in blood ortissue as part of a clinical testing procedure, e.g., to determine theefficacy of a given treatment regimen. For example, detection can befacilitated by coupling an ALK7-binding protein to a detectablesubstance. Examples of detectable substances include various enzymes,prosthetic groups, fluorescent materials, luminescent materials,bioluminescent materials, and/or radioactive materials. Examples ofsuitable enzymes include horseradish peroxidase, alkaline phosphatase,β-galactosidase, or acetylcholinesterase; examples of suitableprosthetic group complexes include streptavidin/biotin andavidin/biotin; examples of suitable fluorescent materials includeumbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; anexample of a luminescent material includes luminol; examples ofbioluminescent materials include luciferase, luciferin, and aequorin;and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S,or ³H.

Pharmaceutical Compositions and Administration Methods

Methods of preparing and administering an ALK7-binding protein to asubject in need thereof are known to or are readily determined by thoseof ordinary skill in the art. The route of administration of theALK7-binding proteins can be, for example, oral, parenteral, byinhalation or topical. The term parenteral includes, e.g., intravenous,intraarterial, intraperitoneal, intramuscular, intraocular,subcutaneous, rectal, or vaginal administration. While all these formsof administration are clearly contemplated as being within the scope ofthe disclosure, another example of a form for administration would be asolution for injection, in particular for intravenous or intraarterialinjection or drip. Usually, a suitable pharmaceutical composition cancomprise a buffer (e.g., acetate, phosphate or citrate buffer), asurfactant (e.g., polysorbate), optionally a stabilizer agent (e.g.,human albumin), etc. In other methods compatible with the teachingsherein, ALK7-binding proteins as provided herein can be delivereddirectly to the organ and/or site of a fibrosis or tumor, therebyincreasing the exposure of the diseased tissue to therapeutic agent. Inone embodiment, the administration is directly to the airway, e.g., byinhalation or intranasal administration.

As discussed herein, ALK7-binding proteins can be administered in apharmaceutically effective amount for the in vivo treatment ofALK7-mediated diseases and conditions such as, obesity, diabetes,metabolic disease, dyslipidemia; cardiovascular disease, type 2diabetes, inflammation, or a cardiovascular, pulmonary, fatty liverdisease, neurologic, and hepatic, or renal disease, and and/cancer. Inthis regard, it will be appreciated that the disclosed ALK7-bindingproteins can be formulated so as to facilitate administration andpromote stability of the active agent. Pharmaceutical compositions inaccordance with the disclosure can comprise a pharmaceuticallyacceptable, non-toxic, sterile carrier such as physiological saline,non-toxic buffers, preservatives and the like. For the purposes of theinstant application, a pharmaceutically effective amount of aALK7-binding protein, conjugated or unconjugated, means an amountsufficient to achieve effective binding to ALK7 and to achieve abenefit, e.g., to ameliorate symptoms of a disease or condition or todetect a substance or a cell. Suitable formulations for use intherapeutic methods disclosed herein are described in Remington'sPharmaceutical Sciences (Mack Publishing Co.) 16th ed. (1980).

Certain pharmaceutical compositions provided herein can be orallyadministered in an acceptable dosage form including, e.g., capsules,tablets, aqueous suspensions or solutions. Certain pharmaceuticalcompositions also can be administered by nasal aerosol or inhalation.Such compositions can be prepared as solutions in saline, employingbenzyl alcohol or other suitable preservatives, absorption promoters toenhance bioavailability, and/or other conventional solubilizing ordispersing agents.

The amount of an ALK7-binding protein (e.g., an antibody thatspecifically binds ALK7) that can be combined with carrier materials toproduce a single dosage form will vary depending upon the subjecttreated and the particular mode of administration. The composition canbe administered as a single dose, multiple doses or over an establishedperiod of time in an infusion. Dosage regimens also can be adjusted toprovide the optimum desired response (e.g., a therapeutic orprophylactic response).

ALK7-binding proteins provided herein can be administered to a human orother subject in accordance with the aforementioned methods of treatmentin an amount sufficient to produce a therapeutic effect. TheALK7-binding proteins provided herein can be administered to such humanor other animal in a conventional dosage form prepared by combining theALK7-binding proteins with a conventional pharmaceutically acceptablecarrier or diluent according to known techniques. The form and characterof the pharmaceutically acceptable carrier or diluent can be dictated bythe amount of active ingredient with which it is to be combined, theroute of administration and other well-known variables. A cocktailcomprising one or more different ALK7-binding proteins can also be used.

Therapeutically effective doses of ALK7-binding compositions fortreatment of an ALK7-mediated disease or condition such as, obesity,diabetes, metabolic disease, dyslipidemia; cardiovascular disease, type2 diabetes, inflammation, or a cardiovascular, pulmonary, fatty liverdisease, neurologic, and hepatic, or renal disease and/or cancer, varydepending upon many different factors, including means ofadministration, target site, physiological state of the subject, whetherthe subject is human or an animal, other medications administered, andwhether treatment is prophylactic or therapeutic. Usually, the subjectis a human, but non-human mammals including transgenic mammals can alsobe treated. Treatment dosages can be titrated using routine methodsknown to those of ordinary skill in the art to optimize safety andefficacy.

To ameliorate the symptoms of a particular disease or condition byadministration of an ALK7-binding protein refers to any lessening,whether permanent or temporary, lasting or transient that can beattributed to or associated with administration of the ALK7-binding.

The disclosure also provides for the use of an ALK7-binding protein,such as, an anti-ALK7 antibody in the manufacture of a medicament forexample, for treating, preventing or ameliorating obesity, diabetes,metabolic disease, dyslipidemia; cardiovascular disease, type 2diabetes, inflammation, or a cardiovascular, pulmonary, fatty liverdisease, neurologic, and hepatic, or renal disease and/or cancer.

Combination Therapies

In some embodiments, an ALK7-binding protein (e.g., an anti-ALK7antibody such as, a full-length ALK7-antibody and an ALK7-bindingantibody fragment, or a variant or derivative thereof) is administeredin combination with one or more other therapies. Such therapies includeadditional therapeutic agents as well as other medical interventions.Exemplary therapeutic agents that can be administered in combinationwith the ALK7-binding proteins provided herein include, but are notlimited to, anti-SDI-fibrotics, corticosteroids, anti-inflammatories,angiotensin converting enzyme inhibitors, angiotensin receptor blockers,diuretics, antidiabetics, immune suppressants, chemotherapeutic agents,anti-metabolites, and/or immunomodulators. In various embodiments, anALK7-binding protein is administered to a subject before, during, and/orafter a surgical excision/removal procedure.

In some embodiments, an ALK7-binding protein (e.g., an anti-ALK7antibody such as, a full-length ALK7-antibody and an ALK7-bindingantibody fragment, or a variant or derivative thereof) is administeredin combination with one or more (a) biguanides (e.g., buformin,metformin, phenformin), (b) insulin, (c) somatostatin, (d)alpha-glucosidase inhibitors (e.g., voglibose, miglitol, acarbose), (e)DPP-IV inhibitors, such as sitagliptin, vildagliptin, alogliptin,saxagliptin (e.g., as disclosed in U.S. Pat. No. 6,699,871B1) (f) LXRmodulators, (g) insulin secretagogues (e.g., acetohexamide, carbutamide,chlorpropamide, glibornuride, gliclazide, glimerpiride, glipizide,gliquidine, glisoxepid, glyburide, glyhexamide, glypinamide,phenbutamide, tolazamide, tolbutamide, tolcyclamide, nateglinide and/orrepaglinide), (k) CB1 inhibitors, such as, rimonabant, taranabant, andcompounds disclosed in Intl. Appl. Publ. Nos. WO03/077847A2 andWO05/000809 A1, or (i). sibutramine, topiramate, orlistat, Qnexa,mevastatin, simvastatin, ezetimibe, atorvastatin, naltrexone,bupriopion, phentermine, hydrochlorothiazide, or losartan.

Diagnostics

The disclosure also provides a diagnostic method useful during diagnosisof ALK7-mediated diseases and conditions (such as, obesity (e.g.,abdominal or visceral obesity); overweight; insulin resistance;metabolic syndrome and/or other metabolic diseases or conditions; alipid disorder such as, low HDL levels, high LDL levels, hyperlipidemia,hypertriglyceridemia or dyslipidemia; lipoprotein aberrations; decreasedtriglycerides; inflammation (e.g., liver inflammation and/orinflammation of adipose tissue), fatty liver disease; non-alcoholicfatty liver disease; hyperglycemia; impaired glucose tolerance (IGT);hyperinsulinemia; high cholesterol (e.g., high LDL levels and/orhypercholesterolemia); cardiovascular disease such as, heart diseaseincluding coronary heart disease, congestive heart failure, stroke,peripheral vascular disease, atherosclerosis; arteriosclerosis, and/orhypertension; Syndrome X; vascular restenosis; neuropathy; retinopathy;neurodegenerative disease; endothelial dysfunction, respiratorydysfunction, renal disease (e.g., nephropathy); pancreatitis; polycysticovarian syndrome; elevated uric acid levels; haemochromatosis (ironoverload); acanthosis nigricans (dark patches on the skin); and/orcancer (e.g., a myeloma (e.g., multiple myeloma, plasmacytoma, localizedmyeloma, or extramedullary myeloma), or an ovarian, breast, colon,endometrial, liver, kidney, pancreatic, gastric, uterine or coloncancer); and/or other disorders/conditions associated with one or moreof the above diseases or conditions, or with too much body fat.), whichinvolves measuring the expression level of ALK7 protein tissue or bodyfluid from an individual and comparing the measured expression levelwith a standard ALK7 expression level in normal tissue or body fluid,whereby an increase in ALK7 expression level compared to the standard isindicative of a disorder treatable by an ALK7-binding protein providedherein, such as a full-length anti-ALK7 antibody and ALK7-bindingantibody fragment as provided herein.

The ALK7-binding proteins provided herein such as, anti-ALK7 antibodies(e.g., full-length ALK7-antibodies and ALK7-binding antibody fragment,and variants and derivatives thereof) can be used to assay ALK7 levelsin a biological sample using classical immunohistological methods knownto those of skill in the art (see, e.g., Jalkanen, et al., J. Cell.Biol. 101:976-985 (1985); Jalkanen et al., J. Cell Biol. 105:3087-3096(1987)). Other antibody-based methods useful for detecting ALK7 proteinexpression include immunoassays, such as the enzyme linked immunosorbentassay (ELISA), immunoprecipitation, or Western blotting.

By “assaying the expression level of ALK7 protein” is intendedqualitatively or quantitatively measuring or estimating the level ofALK7 protein in a first biological sample either directly (e.g., bydetermining or estimating absolute protein level) or relatively (e.g.,by comparing to the disease associated polypeptide level in a secondbiological sample). The ALK7 protein expression level in the firstbiological sample can be measured or estimated and compared to astandard ALK7 protein level, the standard being taken from a secondbiological sample obtained from an individual not having the disorder orbeing determined by averaging levels from a population of individualsnot having the disorder. As will be appreciated in the art, once the“standard” ALK7 protein level is known, it can be used repeatedly as astandard for comparison.

By “biological sample” is intended any biological sample obtained froman individual, cell line, tissue culture, or other source of cellspotentially expressing ALK7. Methods for obtaining tissue biopsies andbody fluids from mammals are known in the art.

Kits Comprising ALK7-Binding Proteins

This disclosure further provides kits that include an ALK7-bindingprotein (e.g., an antibody that specifically binds ALK7 such as, afull-length ALK7-antibody and an ALK7-binding antibody fragment, andvariants and derivatives thereof) in suitable packaging, and writtenmaterial and that can be used to perform the methods described herein.The written material can include any of the following information:instructions for use, discussion of clinical studies, listing of sideeffects, scientific literature references, package insert materials,clinical trial results, and/or summaries of these and the like. Thewritten material can indicate or establish the activities and/oradvantages of the composition, and/or describe dosing, administration,side effects, drug interactions, or other information useful to thehealth care provider. Such information can be based on the results ofvarious studies, for example, studies using experimental animalsinvolving in vivo models and/or studies based on human clinical trials.The kit can further contain another therapy (e.g., another agent) and/orwritten material such as that described above that serves to provideinformation regarding the other therapy (e.g., the other agent).

In certain embodiments, a kit comprises at least one purifiedALK7-binding protein in one or more containers. In some embodiments, thekits contain all of the components necessary and/or sufficient toperform a detection assay, including all controls, directions forperforming assays, and/or any necessary software for analysis andpresentation of results.

Immunoassays

ALK7-binding proteins (e.g., antibodies that specifically bind ALK7 andACTRIIA/B-binding fragments of antibodies that specifically bind ALK7,and variants, or derivatives thereof) can be assayed for immunospecificbinding by any method known in the art. The immunoassays that can beused include, but are not limited to, competitive and non-competitiveassay systems using techniques such as Western blots, radioimmunoassays(REA), ELISA (enzyme linked immunosorbent assay), “sandwich”immunoassays, immunoprecipitation assays, precipitin reactions, geldiffusion precipitin reactions, immunodiffusion assays, agglutinationassays, complement-fixation assays, immunoradiometric assays,fluorescent immunoassays, or protein A immunoassays. Such assays areroutine and known in the art (see, e.g., Ausubel et al., eds, (1994)Current Protocols in Molecular Biology (John Wiley & Sons, Inc., NY)Vol. 1, which is herein incorporated by reference in its entirety).

ALK7-binding proteins (e.g., antibodies that specifically binds ALK7 andan ActRII receptor (e.g., ActRIIA or ActRIIB)-binding fragments ofantibodies that specifically bind ALK7, and variants, or derivativesthereof) provided herein can be employed histologically, as inimmunofluorescence, immunoelectron microscopy or non-immunologicalassays, for in situ detection of ALK7 or conserved variants or peptidefragments thereof. In situ detection can be accomplished according tomethods known in the art. Those of ordinary skill in the art will beable to determine operative and optimal assay conditions for eachdetermination by employing routine experimentation. Methods suitable fordetermination of binding characteristics of an ALK7-binding protein aredescribed herein or otherwise known in the art. Equipment and softwaredesigned for such kinetic analyses are commercially available (e.g.,BIACORE®, BIAevaluation® software, GE Healthcare; KINEXA® Software,Sapidyne Instruments).

Unless otherwise indicated, the practice of the disclosure employsconventional techniques of cell biology, cell culture, molecularbiology, transgenic biology, microbiology, recombinant DNA, andimmunology, which are within the skill of the art.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES

The foregoing description of the specific embodiments will so fullyreveal the general nature of the disclosure that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific embodiments, without undueexperimentation, without departing from the general concept of thepresent disclosure. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed embodiments, based on the teaching and guidance presentedherein. It is to be understood that the phraseology or terminologyherein is for the purpose of description and not of limitation, suchthat the terminology or phraseology of the present specification is tobe interpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present disclosure should not be limited byany of the above-described exemplary embodiments, but should be definedonly in accordance with the following claims and their equivalents.

All publications, patents, patent applications, and/or other documentscited in this application are incorporated by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent, patent application, and/or other document wereindividually indicated to be incorporated by reference for all purposes.

Example 1. Selection, Characterization and Production of ALK7-BindingAntibodies

A multi-round selection procedure was used to select for human IgGantibodies that bind ALK7 with high affinity which is detailed below.

Materials and Methods

Human ALK7-Fc comprising protein was biotinylated using the EZ-LinkSulfo-NHS-Biotinylation Kit from Pierce. Goat anti-human F(ab′)₂kappa-FITC (LC-FITC), Extravidin-PE (EA-PE) and streptavidin-633(SA-633) were obtained from Southern Biotech, Sigma and MolecularProbes, respectively. Streptavidin MicroBeads and MACS LC separationcolumns were purchased from Miltenyi Biotec.

Experiments were performed using a Biacore T100/T200 biosensor(Biacore/GE Healthcare) at 25° C. and 37° C. ALK7antibodies werecaptured on custom made FAB chip. A concentration series of ALK7-Fccomprising protein was injected over the flow cells at a flow rate of 50μl/ml. To obtain kinetic rate constants the corrected data were fit to a1:1 interaction model using BiaEvaluation software (GE Healthcare). Theequilibrium binding constant KD was determined by the ratio of bindingrate constants kd/ka.

Eight naïve human synthetic yeast libraries each of ˜10⁹ diversity werepropagated as described previously (see, e.g., WO09/036379; WO10/105256;WO12/009568). For the first two rounds of selection, a magnetic beadsorting technique utilizing the Miltenyi MACs system was performed, asdescribed (see, e.g., Siegel et al., J. Immunol. Meth. 286(1-2):141-153(2004)). Briefly, yeast cells (˜10¹⁰ cells/library) were incubated with3 ml of 10 nM biotinylated ALK7-Fc comprising protein for 15 minute atroom temperature in FACS wash buffer (phosphate-buffered saline(PBS)/0.1% bovine serum albumin (BSA)). After washing once with 50 mlice-cold wash buffer, the cell pellet was resuspended in 40 mL washbuffer, and Streptavidin MicroBeads (500 μl) were added to the yeast andincubated for 15 minutes at 4° C. Next, the yeast were pelleted,resuspended in 5 mL wash buffer, and loaded onto a Miltenyi LS column.After the 5 mL was loaded, the column was washed 3 times with 3 ml FACSwash buffer. The column was then removed from the magnetic field, andthe yeast were eluted with 5 mL of growth media and then grownovernight. The following rounds of sorting were performed using flowcytometry. Approximately 1×10⁸ yeast were pelleted, washed three timeswith wash buffer, and incubated with decreasing concentrations ofbiotinylated ALK7-Fc comprising protein (100 to 1 nM) under equilibriumconditions at room temperature. Yeast were then washed twice and stainedwith LC-FITC (diluted 1:100) and either SA-633 (diluted 1:500) or EA-PE(diluted 1:50) secondary reagents for 15 minutes at 4° C. After washingtwice with ice-cold wash buffer, the cell pellets were resuspended in0.4 mL wash buffer and transferred to strainer-capped sort tubes.Sorting was performed using a FACS ARIA sorter (BD Biosciences) and sortgates were assigned to select for specific binders relative to abackground control. Subsequent rounds of selection were employed inorder to reduce the number non-specific reagent binders utilizingsoluble membrane proteins from CHO cells (See, e.g., WO14/179363 and Xuet al., Protein Eng. Des. Sel. 26(10):663-670 (2013)), and to identifybinders with improved affinity to ALK7 using the ALK7-Fc comprisingprotein. After the final round of sorting, yeast were plated andindividual colonies were picked for characterization and for nominationof clones for affinity maturation.

Antibody Production and Purification

In order to produce sufficient amounts of selected antibodies forfurther characterization, the yeast clones were grown to saturation andthen induced for 48 h at 30° C. with shaking. After induction, yeastcells were pelleted and the supernatants were harvested forpurification. IgGs were purified using a Protein A column and elutedwith acetic acid, pH 2.0. Fab fragments were generated by papaindigestion and purified over KappaSelect (GE Healthcare LifeSciences).

ForteBio K_(D) Measurements

ForteBio affinity measurements of selected antibodies were performedgenerally as previously described (see, e.g., Estep et al., Mabs,5(2):270-278 (2013)). Briefly, ForteBio affinity measurements wereperformed by loading IgGs on-line onto AHQ sensors. Sensors wereequilibrated off-line in assay buffer for 30 minutes and then monitoredon-line for 60 seconds for baseline establishment. Sensors with loadedIgGs were exposed to 100 nM antigen for 5 minutes, afterwards they weretransferred to assay buffer for 5 minutes for off-rate measurement.Kinetics were analyzed using the 1:1 binding model.

Octet Red384 Epitope Binning/Ligand Blocking

Epitope binning/ligand blocking of selected antibodies was performedusing a standard sandwich format cross-blocking assay. Controlanti-target IgG was loaded onto AHQ sensors and unoccupied Fc-bindingsites on the sensor were blocked with an irrelevant human IgG1 antibody.The sensors were then exposed to 100 nM target antigen followed by asecond anti-target antibody or ligand. Data was processed usingForteBio's Data Analysis Software 7.0. Additional binding by the secondantibody or ligand after antigen association indicates an unoccupiedepitope (non-competitor), while no binding indicates epitope blocking(competitor or ligand blocking).

Size Exclusion Chromatography

A TSKgel SuperSW mAb HTP column (22855) was used for fast SEC analysisof yeast-produced mAbs at 0.4 mL/minute with a cycle time of 6 min/run.200 mM Sodium Phosphate and 250 mM Sodium Chloride was used as themobile phase.

Dynamic Scanning Fluorimetry

10 uL of 20× Sypro Orange was added to 20 uL of 0.2-1 mg/mL mAb or Fabsolution. An RT-PCR instrument (BioRad CFX96 RT PCR) was used to rampthe sample plate temperature from 40° to 95° C. at 0.5° C. increment,with a 2 minute equilibration at each temperature. The negative of thefirst derivative for the raw data was used to extract Tm.

Example 2. Characterization of ALK7-Binding Antibodies

Exemplary ALK7-binding proteins generated according to the previousexample were further characterized by sequence, SPR, and cell-basedlipolysis inhibition assay analyses.

Sequences of exemplary ALK7-binding antibodies generated according tothe methods described in Example 1 are presented in Table 1A (exemplaryCDR sequences are underscored).

TABLE 1A Exemplary ALK7-binding proteins G04 VH FR1QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 6) VH CDR1SYAIS (SEQ ID NO: 1) VH FR2 WVRQAPGQGLEWMG (SEQ ID NO: 7) VH CDR2GIIPIFGTASYAQKFQG (SEQ ID NO: 2) VH FR3RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 8) VH CDR3TPYYDSSGYLDV (SEQ ID NO: 3) VH FR4 WGQGTMVTVSS (SEQ ID NO: 9) VH ABRsABR1: GTFSSYAIS (SEQ ID NO: 73) ABR2: GIIPIFGTASYAQKFQG (SEQ ID NO: 74)ABR3: ARTPYYDSSGYLDV (SEQ ID NO: 75) VH DNACAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAGCAAGCTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAACTCCTTACTACGACAGCAGCGGATACCTAGACGTATGGGGTCAGGGTACAATGGTCACCGTCTCCTCA (SEQ ID NO: 5) VH ProteinQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARTPYYDSSGYLDVWGQGTMVTVSS (SEQ ID NO: 4) VL FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 15) VL CDR1QASQDISNYLN (SEQ ID NO: 10) VL FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 16)VL CDR2 DASNLAT (SEQ ID NO: 11) VL FR3GVPSRFSGSGSGTDFTFTISSLQPEDIATYYC (SEQ ID NO: 17) VL CDR3QQSLDLPPT (SEQ ID NO: 12) VL FR4 FGGGTKVEIK (SEQ ID NO: 18) VL DNAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCGAGTCAGGACATTAGCAACTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTACGATGCATCCAATTTGGCAACAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTACTGTCAGCAGTCCCTCGACCTCCCTCCTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAA (SEQ ID NO: 14) VL ProteinDIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLATGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQSLDLPPTFGGGTKVEIK (SEQ ID NO:  13) C02VH FR1 QLQLQESGPGLVKPSETLSLTCTVSGGSIS (SEQ ID NO: 24) VH CDR1SSSYYWG (SEQ ID NO: 19) VH FR2 WIRQPPGKGLEWIG (SEQ ID NO: 25) VH CDR2NIYYSGSTYYNPSLKS (SEQ ID NO: 20) VH FR3RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR (SEQ ID NO: 26) VH CDR3DGRYQSATADYYYGMDV (SEQ ID NO: 21) VH FR4 WGQGTTVTVSS (SEQ ID NO: 27)VH ABRS ABR1: GSISSSSYYWG (SEQ ID NO: 76)ABR2: NIYYSGSTYYNPSLKS (SEQ ID NO: 77)ABR3: ARDGRYQSATADYYYGMDV (SEQ ID NO: 78) VH DNACAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGACACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGTAGTTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAACATCTATTATAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCGGTGTACTACTGCGCCAGAGACGGCAGATACCAAAGCGCCACAGCCGATTACTATTACGGTATGGATGTCTGGGGCCAGGGAAGAACTGTCACCGTCTCCTCA (SEQ ID NO: 23) VH ProteinQLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGRYQSATADYYYGMDVWGQGTTVTVSS (SEQ ID NO: 22) VL FR1 EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 33)VL CDR1 RASQSVSSSYLA (SEQ ID NO: 28) VL FR2WYQQKPGQAPRLLIY (SEQ ID NO: 34) VL CDR2 GASSRAT (SEQ ID NO: 29) VL FR3GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 35) VL CDR3QQVFSYPFT (SEQ ID NO: 30) VL FR4 FGGGTKVEIK (SEQ ID NO: 36) VL DNAGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGGTCTTCAGTTACCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAA (SEQ ID NO: 32) VL ProteinEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQVFSYPFTFGGGTKVEIK (SEQ ID NO:  31) D04VH FR1 EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 42) VH CDR1SYAMS (SEQ ID NO: 37) VH FR2 WVRQAPGKGLEWVS (SEQ ID NO: 43) VH CDR2AISGSGGSTYYADSVKG (SEQ ID NO: 38) VH FR3RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 44) VH CDR3RYRGVSFDI (SEQ ID NO: 39) VH FR4 WGRGTMVTVSS (SEQ ID NO: 45) VH ABRsABR1: FTFSSYAMS (SEQ ID NO: 79) ABR2: AISGSGGSTYYADSVKG (SEQ ID NO: 80)ABR3: ARRYRGVSFDI (SEQ ID NO: 81) VH DNAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGGAGATACAGAGGAGTGTCATTCGACATATGGGGTCGGGGTACAATGGTCACCGTCTCCTCA (SEQ ID NO: 41)VH Protein EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRYRGVSFDIWGRGTMVTVSS(SEQ ID NO: 40) VL FR1 EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 51) VL CDR1RASQSVSSSYLA (SEQ ID NO: 46) VL FR2 WYQQKPGQAPRLLIY (SEQ ID NO: 52)VL CDR2 GASSRAT (SEQ ID NO: 47) VL FR3GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 53) VL CDR3 QQDSIDIT (SEQ ID NO: 48) VL FR4 FGGGTKVEIK (SEQ ID NO: 54) VL DNAGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGGACTCCATCGACATCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAA (SEQ ID NO: 50) VL ProteinEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQDSIDITPGGGTKVEIK (SEQ ID NO:  49) H03VH FR1 EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 60) VH CDR1SYAMS (SEQ ID NO: 55) VH FR2 WVRQAPGKGLEWVS (SEQ ID NO: 61) VH CDR2AISGSGGSTYYADSVKG (SEQ ID NO: 56) VH FR3RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 62) VH CDR3PYQARAFDI (SEQ ID NO: 57) VH FR4 WGQGTMVTVSS (SEQ ID NO: 63) VH ABRsABR1: FTFSSYAMS (SEQ ID NO: 82) ABR2: AISGSGGSTYYADSVKG (SEQ ID NO: 83)ABR3: ARPYQARAFDI (SEQ ID NO: 84) VH DNAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGACCTTACCAAGCCAGAGCCTTTGATATTTGGGGTCAGGGTACAATGGTCACCGTCTCCTCA (SEQ ID NO: 59)VH Protein EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARPYQARAFDIWGQGTMVTVSS (SEQ ID NO: 58) VL FR1 EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 51) VL CDR1RASQSVSSSFLA (SEQ ID NO: 64) VL FR2 WYQQKPGQAPRLLIY (SEQ ID NO: 52)VL CDR2 GASSRAT (SEQ ID NO: 65) VL FR3GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 53) VL CDR3QQYVVAPIT (SEQ ID NO: 66) VL FR4 FGGGTKVEIK (SEQ ID NO: 54) VL DNAGAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTTCTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAGTACGTCGTCGCCCCTATCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAA (SEQ ID NO: 68) VL ProteinEIVLTQSPGTLSLSPGERATLSCRASQSVSSSFLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYVVAPITFGGGTKVEIK (SEQ ID NO:  67)

TABLE 1B Additional exemplary ALK7-binding proteins J01 VH FR1EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 42) VH CDR1SYAMS (SEQ ID NO: 37) VH FR2 WVRQAPGKGLEWVS (SEQ ID NO: 43) VH CDR2AISGSGGSTYYADSVKG (SEQ ID NO: 56) VH FR3RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK (SEQ ID NO: 93) VH CDR3PSYQPIY (SEQ ID NO: 90) VH FR4 WGQGTLVTVSS (SEQ ID NO: 94) VH ABRsABR1: FRFSSYAMS (SEQ ID NO: 153)ABR2: AISGSGGSTYYADSVKG (SEQ ID NO: 154)ABR3: AKPSYQPIY (SEQ ID NO: 155) VH DNAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGTAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAAGCCTTCTTACCAACCAATATACTGGGGACAGGGTACATTGGTCACCGTCTCCTCA (SEQ ID NO: 151) VH ProteinEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPSYQPIYWGQGTLVTVSS (SEQ ID NO: 152) VL FR1 DIQMTQSPSSVSASVGDRVTITC (SEQ ID NO: 100) VL CDR1RASQGISSWLA (SEQ ID NO: 95) VL2 FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 16)VL CDR2 AASSLQS (SEQ ID NO: 96) VL FR3GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 101) VL CDR3QQAASYPLT (SEQ ID NO: 97) VL FR4 FGGGTKVEI (SEQ ID NO: 18) VL DNAGACATCCAGATGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGCTTAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGGCAGCCAGTTACCCTCTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAA (SEQ ID NO: 99) VL ProteinDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAASYPLTFGGGTKVEIK (SEQ ID NO:  98) KO1VH FR1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 6) VH CDR1NYAIS (SEQ ID NO: 156) VH FR2 WVRQAPGQGLEWMG (SEQ ID NO: 7) VH CDR2GIIPIFGTANYAQKFQG (SEQ ID NO: 157) VH FR3RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 8) VH CDR3DPREYIHVFDI (SEQ ID NO: 104) VH FR4 WGQGTMVTVSS (SEQ ID NO: 9) VH ABRsABR1: GTFSNYAIS (SEQ ID NO: 160)ABR2: GIIPIFGTANYAQKFQG (SEQ ID NO: 161)ABR3: ARDPREYIHVFDI (SEQ ID NO: 162) VH DNACAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAACTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAGATCCAAGAGAATATATCCACGTATTCGACATATGGGGTCAGGGTACAATGGTCACCGTCTCCTCA (SEQ ID NO: 158) VH ProteinQVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDPREYIHVFDIWGQGTMVTVSS(SEQ ID NO: 159) VL FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 15) VL CDR1RASQSISSYLN (SEQ ID NO: 107) VL FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 16)VL CDR2 GASSLQS (SEQ ID NO: 108) VL FR3GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 112) VL CDR3QQAYSFPWT (SEQ ID NO: 109) VL FR4 FGGGIKVEIK (SEQ ID NO: 113) VL DNAGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGGTGCAGCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAGCAAGCATACAGTTTCCCTTGGACTTTTGGCGGAGGGATCAAGGTTGAGATCAAA (SEQ ID NO: 111) VL ProteinDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAYSFPWTFGGGIKVEIK (SEQ ID NO:  110) L01VH FR1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 6) VH CDR1SYAIS (SEQ ID NO: 1) VH FR2 WVRQAPGQGLEWMG (SEQ ID NO: 7) VH CDR2SIIPIFGTANYAQKFQG (SEQ ID NO: 163) VH FR3RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 8) VH CDR3DPVGARYEVFDY (SEQ ID NO: 164) VH FR4 WGQGTLVTVSS (SEQ ID NO: 94) VH ABRsABR1: GTFSSYAIS (SEQ ID NO: 172)ABR2: SIIPIFGTANYAQKFQG (SEQ ID NO: 173)ABR3: ARDPVGARYEVFDY (SEQ ID NO: 174) VH DNACAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAAGCATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAGACCCTGTCGGAGCAAGATACGAGGTTTTCGATTACTGGGGACAGGGTACATTGGTCACCGTCTCCTCA (SEQ ID NO: 165) VH ProteinQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGSIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDPVGARYEVFDYWGQGTLVTVSS (SEQ ID NO: 166) VL FR1 EIVMTQSPATLSVSPGERATLSC (SEQ ID NO: 150) VL CDR1RASQSVSSNLA (SEQ ID NO: 167) VL FR2 WYQQKPGQAPRLLIY (SEQ ID NO: 34)VL CDR2 SASTRAT (SEQ ID NO: 168) VL FR3GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC (SEQ ID NO: 151) VL CDR3QQANTFPLT (SEQ ID NO: 169) VL FR4 FGGGTKVEIK (SEQ ID NO: 54) VL DNAGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGGCCAATACCTTCCCTCTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAA (SEQ ID NO: 170) VL ProteinEIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYSASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQANTFPLTFGGGTKVEIK (SEQ ID NO:  171)

SPR (BIACORE™-based analysis) and a cell-based lipolysis inhibitionassay was used to more fully characterize and exemplary set of theALK7-binding proteins described in Table 1A, Table 1B, or Table 3.

Surface Plasmon Resonance Analysis—

Experiments were performed using a Biacore T100/T200 biosensor(Biacore/GE Healthcare) at 25 and 37° C. ALK7 antibodies were capturedon custom made FAB chip. A concentration series of ALK7-Fc comprisingprotein was injected over the flow cells at a flow rate of 50 μl/ml. Toobtain kinetic rate constants the corrected data were fit to a 1:1interaction model using BiaEvaluation software (GE Healthcare). Theequilibrium binding constant KD was determined by the ratio of bindingrate constants kd/ka.

Lipolysis Inhibition Assay

Lipolysis is the hydrolysis of triglycerides within the cell intoglycerol and free fatty acids. The glycerol and free fatty acids arethen released into the bloodstream or culture media. While lipolysisoccurs in essentially all cells, it is most abundant in white and brownadipocytes. 3T3-L1 cells (supplied by ATCC; ATCC® CL-173™) were grown inDulbecco's Modified Eagle Medium (ATCC; ATCC® 30-2002™) containing 10%Bovine Serum (Life Technologies; 16170-060) until reaching confluency.To induce differentiation, at 2 days post-confluency medium was replacedby fresh Dulbecco's Modified Eagle Medium (ATCC; ATCC® 30-2002™)containing 10% fetal Bovine serum (Life Technologies; Ser. No.10/082,147), dexamethasone (Sigma, D8893), IBMX (Sigma, 17018) andinsulin (Sigma, 10516) for 2 weeks. Accumulation of lipid droplets onthe cells, as determined by microscopy, was used to confirm a completedifferentiation into mature adipocyte cells. Adipocytes were treatedovernight with vehicle (PBS), activin B (50 ng/ml) or co-treated withactivin B (50 ng/ml) and ALK7antibodies (5 μg/ml). Cells were washed twotimes with PBS and incubated with lipolysis assay buffer (supplied byAbcam; ab185433). Lipolysis assay buffer was collected after 3 hours andglycerol levels were measured according to manufacturer's instruction(Abcam; ab185433).

Results of the SPR are presented in Table 2A and 2B and cell-basedlipolysis inhibition assay for exemplary ALK-7 binding proteins arepresented in Table 2A.

Results of the SPR and cell-based lipolysis inhibition assay forexemplary ALK-7 binding proteins are presented in Table 3.

TABLE 2A Binding characterization and activity of exemplary ALK7-bindingproteins Increase in lipolysis Binding to human ALK7-Fc comprisingprotein Binding to rat Alk7-Fc comprising protein activity k_(on)(M⁻¹s⁻¹) k_(off) (s⁻¹) K_(D) (nM) k_(on) (M⁻¹s⁻¹) koff (s⁻¹) K_(D) (nM)(%) C02 2.31 × 10⁴ 1.42 × 10⁻³ 61.2 N/A 55.8% D04 7.40 × 10⁴ 3.78 × 10⁻³51.1 6.13 × 10³ 1.38 × 10⁻³ 225 109.2% G04 8.96 × 10⁴ 2.22 × 10⁻² 247N/A 45.8% H03 1.79 × 10⁵ 4.32 × 10⁻³ 24.1 1.07 × 10⁴ 1.54 × 10⁻³ 14491.8%

TABLE 2B Binding characterization of exemplary ALK7-binding proteinsBinding to human ALK7-Fc comprising protein Binding to rat Alk7-Fccomprising protein k_(on) (M⁻¹s⁻¹) k_(off) (s⁻¹) K_(D) (nM) k_(on)(M⁻¹s⁻¹) koff (s⁻¹) K_(D) (nM) J01 N/A 1.62 × 10⁴ 4.78 × 10⁻² 29.5 K014.56 × 10⁴ 9.16 × 10⁻³ 200.8 1.71 × 10⁴ 1.39 × 10⁻⁴ 8.14 L01 2.43 × 10⁴3.67 × 10⁴  15.1 1.18 × 10⁴ 2.71 × 10⁻⁴ 22.9

ALK7 signaling is thought to suppress lipolysis and to consequently leadto fat accumulation in adipocytes and adipose tissue. The ability ofantibodies H03, D04, C02, and 004 to interfere with ALK7-mediatedinhibition of lipolysis was assessed in a cell-based lipolysisinhibition assay. The antibodies H03, D04, C02, and 004 increasedlipolysis activity by 91.8%, 109.2%, 55.8%, and 45.8%, respectively.Accordingly, these data indicate that ALK7 antibodies can be used toantagonize ALK7-mediated suppression of lipolysis and thereby increasefatty acid breakdown in adipocytes. Together, these data indicate thatALK7 antibodies may be used to treat a variety of disorder or conditionsassociated with low lipolysis activity and/or excessive fatty acidaccumulation in cells, particularly adipocytes (adipose cells),including for example, obesity, diabetes, insulin resistance; metabolicsyndrome fatty liver disease and other metabolic diseases or conditions.

The extracellular domain of human ALK7 (SEQ ID NO: 85) and rat ALK7 (SEQID NO: 86) share 97% sequence identity. The binding of antibodies 1-103,004. C02 and D04 to human ALK7 and rat ALK7 was determined using SPR.The antibodies H03, D04, K01, and L01 bind to both human ALK7 and ratALK7. F03 and C02 only bound human ALK7. J01 only bound rat ALK7.

Example 3. Binding Optimization of ALK7 Antibodies

Binding optimization of naïve clones was carried out utilizing threematuration strategies: light chain diversification; diversification ofCDRH and/CDR1-12; and performing sequential VH and VL mutagenesis.

Light chain diversification: Heavy chain plasmids were extracted naïveoutputs (described above) and transformed into a light chain librarywith a diversity of 1×10⁶. Selections were performed as described abovewith one round of MACS sorting and two rounds of FACS sorting using 10nM or 1 nM biotinylated ALK7-Fc antigen (for respective rounds.

CDRH1 and CDRH2 selection: The CDRH3s from clones selected from thelight chain diversification procedure of was recombined into a premadelibrary with CDRH1 and CDRH2 variants of a diversity of 1×10⁸ andselections were performed using ALK7, as described above. Affinitypressures were applied by incubating the biotinylated antigen-antibodyyeast complex with unbiotinylated antigen for different amounts of timeto select for the highest affinity antibodies.

VHmut/VKmut selection: Clones obtained from the CDRH1 and CDRH2selection procedure were subject to additional rounds of affinitymaturation via error prone PCR-based mutagenesis of the heavy chainand/or light chain. Selections were performed using ALK7 as antigengenerally as described in Example 2 above, but with the addition ofemploying FACS sorting for all selection rounds. Antigen concentrationwas reduced and cold antigen competition times were increased topressure further for optimal affinity.

The sequence of exemplary optimized ALK7 antibodies is provided in Table3.

TABLE 3 Exemplary affinity matured ALK7-binding proteins J02 VH FR1EVQLLESGGGLVQPGGSLRLSCAASGFTFS (SEQ ID NO: 42) VH CDR1VYAMS (SEQ ID NO: 88) VH FR2 WVRQAPGKGLEWVS (SEQ ID NO: 43) VH CDR2AISGSGDSTVYADSVKG (SEQ ID NO: 89) VH FR3RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK (SEQ ID NO: 93) VH CDR3PSYQPIY (SEQ ID NO: 90) VH FR4 WGQGTLVTVSS (SEQ ID NO: 94) VH ABRsABR1: FTFSVYAMS (SEQ ID NO: 175)ABR2: AISGSGDSTVYADSVKG (SEQ ID NO: 176)ABR3: AKPSYQPIY (SEQ ID NO: 177) VH DNAGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTTCGGTGTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGAAGTGGTGATAGCACAGTGTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAAGCCTTCTTACCAACCAATATACTGGGGACAGGGTACATTGGTCACCGTCTCCTCA (SEQ ID NO: 92) VH ProteinEVQLLESGGGLVQPGGSLRLSCAASGFTFSVYAMSWVRQAPGKGLEWVSAISGSGDSTVYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPSYQPIYWGQGTLVTVSS (SEQ  ID NO: 91)VL FR1 DIQMTQSPSSVSASVGDRVTITC (SEQ ID NO: 100) VL CDR1RASQGISSWLA (SEQ ID NO: 95) VL FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 16)VL CDR2 AASSLQS (SEQ ID NO: 96) VL FR3GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 101) VL CDR3QQAASYPLT (SEQ ID NO: 97) VL FR4 FGGGTKVEIK (SEQ ID NO: 18) VL DNAGACATCCAGATGACCCAAAGCCCTAGTTCCGTCTCTGCAAGCGTGGGAGATAGGGTCACAATCACATGTAGAGCTTCTCAGGGGATCTCTAGCTGGCTGGCTTGGTATCAGCAGAAGCCCGGTAAGGCCCCAAAGCTCTTGATATACGCCGCCTCTTCTCTTCAATCTGGGGTGCCATCCCGCTTCTCAGGGAGCGGTAGCGGGACCGATTTCACCCTCACTATCAGCAGCCTGCAGCCTGAAGACTTTGCTACCTACTACTGCCAGCAAGCCGCTTCTTATCCTCTGACTTTCGGTGGGGGTACTAAAGTGGAGATTAAA (SEQ ID NO: 99) VL ProteinDIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAASYPLTFGGGTKVEIK (SEQ ID NO:  98) KO2VH FR1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 6) VH CDR1SSAIG (SEQ ID NO: 102) VH FR2 WVRQAPGQGLEWMG (SEQ ID NO: 7) VH CDR2GIWPIFGTALYAQKFQG (SEQ ID NO: 103) VH FR3RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 8) VH CDR3DPREYIHVFDI (SEQ ID NO: 104) VH FR4 WGQGTMVTVSS (SEQ ID NO: 9) VH ABRsABR1: GTFSSSAIG (SEQ ID NO: 178)ABR2: GIWPIFGTALYAQKFQG (SEQ ID NO: 179)ABR3: ARDPREYIHVFDI (SEQ ID NO: 180) VH DNACAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCAGCAGTGCTATCGGGTGGGTGCGAGAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCTGGCCTATCTTTGGTACAGCACTTTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAGATCCAAGAGAATATATCCACGTATTCGACATATGGGGTCAGGGTACAATGGTCACCGTCTCCTCA (SEQ ID NO: 106) VH ProteinQVQLVQSGAEVKKPGSSVKVSCKASGGTFSSSAIGWVRQAPGQGLEWMGGIWPIFGTALYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDPREYIHVFDIWGQGTMVTVSS (SEQ ID NO: 105) VL FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 15) VL CDR1RASQSISSYLN (SEQ ID NO: 107) VL FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 16)VL CDR2 GASSLQS (SEQ ID NO: 108) VL FR3GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 112) VL CDR3QQAYSFPWT (SEQ ID NO: 109) VL FR4 FGGGIKVEIK (SEQ ID NO: 113) VL DNAGATATTCAGATGACACAGTCACCTAGCAGTCTGAGCGCATCAGTGGGTGATCGAGTGACAATCACTTGTAGAGCTTCCCAGTCTATTAGCTCATACCTGAACTGGTATCAGCAAAAGCCTGGGAAGGCTCCTAAGCTGTTGATCTATGGAGCATCTAGCCTGCAGTCCGGCGTGCCATCCCGCTTCAGCGGGAGCGGCTCCGGGACCGATTTTACCCTGACAATCTCTAGCCTGCAGCCTGAAGATTTTGCAACCTACTACTGCCAGCAGGCATACAGCTTCCCCTGGACATTCGGAGGTGGCATAAAAGTTGAAATCAAA (SEQ ID NO: 111) VL ProteinDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAYSFPWTFGGGIKVEIK (SEQ ID NO:  110) G05VH FR1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFS (SEQ ID NO: 6) VH CDR1GQAIS (SEQ ID NO: 114) VH FR2 WVRQAPGQGLEWMG (SEQ ID NO: 7) VH CDR2GIIPSFGTARYAQKFQG (SEQ ID NO: 115) VH FR3RVTITADESTSTAYMELSSLRSEDTAVYYCAR (SEQ ID NO: 119) VH CDR3TPYYDSSGYLDV (SEQ ID NO: 116) VH FR4 WGQGTMVTVS (SEQ ID NO: 120) VH ABRsABR1: GTFSGQAIS (SEQ ID NO: 181)ABR2: GIIPSFGTARYAQKFQG (SEQ ID NO: 182)ABR3: ARTPYYDSSGYLDV (SEQ ID NO: 183) VH DNACAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTCAGCGGTCAGGCTATCAGCTGGGTGCGAGAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGATCATCCCTTCGTTTGGTACAGCACGGTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAACTCCTTACTACGACAGCAGCGGATACCTAGACGTATGGGGTCAGGGTACAATGGTCACCGTCTCCTCA (SEQ ID NO: 118) VH ProteinQVQLVQSGAEVKKPGSSVKVSCKASGGTFSGQAISWVRQAPGQGLEWMGGIIPSFGTARYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARTPYYDSSGYLDVWGQGTMVTVS (SEQ ID NO: 117) VL FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 15) VL CDR1QASHDIDNYLN (SEQ ID NO: 121) VL FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 16)VL CDR2 YASNLKT (SEQ ID NO: 122) VL FR3GVPSRFSGSGSGTDFTFTISSLQPEDIATYYC (SEQ ID NO: 17) VL CDR3QQSRASPPT (SEQ ID NO: 123) VL FR4 FGGGTKVEIK (SEQ ID NO: 18) VL DNAGACATCCAGATGACACAGTCCCCTAGCAGCTTGTCAGCCTCAGTGGGCGATAGAGTGACCATCACCTGTCAAGCCAGCCATGATATAGACAACTATCTCAATTGGTACCAGCAGAAACCAGGCAAGGCACCAAAGCTCCTGATCTATTACGCCTCAAACCTTAAGACCGGCGTCCCAAGCCGGTTTTCAGGCAGCGGCAGCGGGACAGATTTCACCTTCACAATTTCATCACTGCAACCTGAGGATATAGCCACTTACTATTGTCAGCAGAGCAGAGCCAGCCCCCCTACCTTCGGCGGCGGTACCAAAGTTGAAATCAAG (SEQ ID NO: 125) VL ProteinDIQMTQSPSSLSASVGDRVTITCQASHDIDNYLNWYQQKPGKAPKLLIYYASNLKTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQSRASPPTFGGGTKVEIK (SEQ ID NO:  124) CO3VH FR1 QLQLQESGPGLVKPSETLSLTCTVS (SEQ ID NO: 130) VH CDR1GGSISSSAY (SEQ ID NO: 125) VH FR2 YWAWIRQPPGKGLEWIG (SEQ ID NO: 131)VH CDR2 SIYLSGSTTYNPSLKS (SEQ ID NO: 126) VH FR3RVTISVDTSKNQFSLKLSSVTAADTAVYYCAR (SEQ ID NO: 26) VH CDR3DGRYQSRSPDYYYGMDV (SEQ ID NO: 127) VH FR4 WGQGTTVTVSS (SEQ ID NO: 27)VH ABRs ABR1: GSISSSAYYWA (SEQ ID NO: 184)ABR2: SIYLSGSTTYNPSLKS (SEQ ID NO: 185)ABR3: ARDGRYQSRSPDYYYGMDV (SEQ ID NO: 186) VH DNACAGCTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGTGCTTACTACTGGGCGTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTTGAGTGGGAGCACCACTTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCGGTGTACTACTGCGCCAGAGACGGCAGATACCAAAGCAGGTCGCCGGATTACTATTACGGTATGGATGTCTGGGGCCAGGGAACAACGGTCACCGTCTCCTCA (SEQ ID NO: 129) VH ProteinQLQLQESGPGLVKPSETLSLTCTVSGGSISSSAYYWAWIRQPPGKGLEWIGSIYLSGSTTYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGRYQSRSPDYYYGMDVWGQGTTVTVSS (SEQ ID NO: 128) VL FR1 EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 33)VL CDR1 KASQSVSSSYLA (SEQ ID NO: 132) VL FR2WYQQKPGQAPRLLIY (SEQ ID NO: 34) VL CDR2 GAFSRAN (SEQ ID NO: 133) VL FR3GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 35) VL CDR3QQLVSYPFT (SEQ ID NO: 134) VL FR4 FGGGTKVEIK (SEQ ID NO: 18) VL DNAGAGATAGTCTTGACCCAGTCACCAGGCACCCTTAGCTTGTCTCCCGGGGAACGCGCCACACTCAGCTGTAAAGCCTCTCAGTCAGTTTCTAGTTCCTACCTCGCTTGGTATCAACAAAAGCCCGGACAAGCACCAAGGCTGTTGATCTACGGAGCTTTCAGTCGCGCAAATGGCATTCCCGACCGATTCTCTGGCAGTGGTAGTGGCACCGACTTCACTCTCACAATTTCTAGGTTGGAACCTGAGGACTTTGCTGTGTACTACTGTCAACAACTGGTTTCTTATCCCTTTACATTCGGTGGCGGCACAAAAGTCGAGATTAAA (SEQ ID NO: 136) VL ProteinEIVLTQSPGTLSLSPGERATLSCKASQSVSSSYLAWYQQKPGQAPRLLIYGAFSRANGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQLVSYPFTFGGGTKVEIK (SEQ ID NO:  135) L02VH FR1 QVQLVQSGAEVKKPGASVKVSCKASGYTFA (SEQ ID NO: 142) VH CDR1GYNMH (SEQ ID NO: 137) VH FR2 WVRQAPGQGLEWVGII (SEQ ID NO: 143) VH CDR2NPNSGW (SEQ ID NO: 138) VH FR3TNYAQKFQGRVTMTRDTSVSAAYMELSRLRSDDTAVYYCAR (SEQ ID NO: 152) VH CDR3DPVGARYEVFDY (SEQ ID NO: 139) VH FR4 WGQGTLVTVSS (SEQ ID NO: 144)VH ABRs ABR1: YTFAGYNMH (SEQ ID NO: 187)ABR2: IINPNSGWTNYAQKFQG (SEQ ID NO: 188)ABR3: ARDPVGARYEVFDY (SEQ ID NO: 189) VH DNACAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGATACACCTTCGCTGGCTACAATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGGTGGGAATTATCAACCCTAACAGTGGTTGGACAAACTATGCACAGAAGTTCCAGGGCAGGGTCACGATGACCAGGGACACGTCCGTCAGCGCAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCGGTGTACTACTGCGCCAGAGACCCTGTCGGAGCAAGATACGAGGTTTTCGATTACTGGGGACAGGGTACATTGGTCACCGTCTCCTCA (SEQ ID NO: 141) VH ProteinQVQLVQSGAEVKKPGASVKVSCKASGYTFAGYNMHWVRQAPGQGLEWVGIINPNSGWTNYAQKFQGRVTMTRDTSVSAAYMELSRLRSDDTAVYYCARDPVGARYEVFDYWGQGTLVTVSS (SEQ ID NO: 140) VL FR1 EIVMTQSPATLSVSPGERATLSC (SEQ ID NO: 150) VL CDR1RASQSVSSALA (SEQ ID NO: 145) VL FR2 WYQQKPGQAPRLLIY (SEQ ID NO: 34)VL CDR2 SAFTRAS (SEQ ID NO: 146) VL FR3GIPARFSGSGSGTEFTLTISSLQSEDFAVYYC (SEQ ID NO: 151) VL CDR3QQAWAFPLT (SEQ ID NO: 147) VL FR4 FGGGTKVEIK (SEQ ID NO: 18) VL DNAGAAATCGTGATGACCCAATCACCTGCCACTCTGTCTGTTAGCCCTGGGGAACGGGCCACCCTCAGTTGTAGGGCCAGTCAGAGTGTTAGTTCAGCTTTGGCTTGGTATCAGCAGAAGCCCGGACAGGCCCCAAGGCTGCTGATCTACTCTGCTTTCACCCGCGCAAGCGGCATCCCCGCACGCTTTAGCGGCTCCGGAAGCGGCACCGAGTTTACTCTTACTATTTCTTCTTTGCAGAGTGAGGATTTTGCCGTGTACTACTGCCAGCAGGCCTGGGCATTTCCACTCACTTTCGGGGGCGGGACCAAGGTCGAAATCAAG (SEQ ID NO: 149) VL ProteinEIVMTQSPATLSVSPGERATLSCRASQSVSSALAWYQQKPGQAPRLLIYSAFTRASGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQAWAFPLTFGGGTKVEIK (SEQ ID NO:  148)

SPR (BIACORE™-based analysis) was used to more fully characterize theaffinity matured ALK7 antibodies described in Table 3.

Surface Plasmon Resonance Analysis—

Experiments were performed using a Biacore T100/T200 biosensor(Biacore/GE Healthcare) at 25 and 37° C. ALK7 antibodies were capturedon custom made FAB chip. A concentration series of ALK7-Fc comprisingprotein was injected over the flow cells at a flow rate of 50 μl/ml. Toobtain kinetic rate constants the corrected data were fit to a 1:1interaction model using BiaEvaluation software (GE Healthcare). Theequilibrium binding constant KD was determined by the ratio of bindingrate constants kd/ka.

Results of the SPR performed as described above are presented in Table4.

TABLE 4 Binding characterization of exemplary affinity matured ALK7antibodies Binding to ALK7-Fc comprising protein (25° C.) k_(on)(M⁻¹s⁻¹) k_(off) (s⁻¹) K_(D) (nM) Parental Antibody J02 2.36 × 10⁴ 1.26× 10⁻⁴ 5.33 J01 K02 2.35 × 10⁴ 2.91 × 10⁻⁴ 12.42 K01 G05 2.99 × 10⁴ 2.59× 10⁻⁵ 0.87 G04 C03 3.83 × 10⁴ 1.27 × 10⁻⁵ 0.33 C02 L02 2.74 × 10⁴ 1.21× 10⁻⁵ 0.44 L01

Example 4. The Effects of ALK7 Abs on Adiposity and Lean Body Mass inObese Mice

Applicants investigated the effect of several human monoclonal ALK7antibodies (ALK7 mAbs) on fat and lean tissue mass in a murine model ofdiet-induced obesity.

Male mice (n=8 per group) were assessed at baseline for fat and leanmuscle amounts using NMR. Mice were then divided into differenttreatments groups: 1) mice fed a standard chow diet (SD) and treatedsubcutaneously twice per week with TBS vehicle; 2) mice fed a high fatdiet (HFD) and treated subcutaneously twice per week with TBS vehicle;3) HDF mice treated subcutaneously twice per week with 10 mg/kg of theALK7 mAb J02; 4) HDF mice treated subcutaneously twice per week with 10mg/kg of the ALK7 mAb K02; 5) HDF mice treated subcutaneously twice perweek with 10 mg/kg of the ALK7 mAb G05; 6) HDF mice treatedsubcutaneously twice per week with 10 mg/kg of the ALK7 mAb C03; and 7)HDF mice treated subcutaneously twice per week with 10 mg/kg of the ALK7mAb L02. After three weeks, mice were again subjected to whole-body NMRscan to assess for fat and lean tissue mass amounts, and thesemeasurements were compared to the baseline amounts of fat and leanmuscle.

TBS treated HFD mice displayed significantly higher amounts of adiposetissue compared to TBS treated SD mice (FIG. 1). On average, treatmentwith each ALK7 mAb resulted in significant less adipose tissueaccumulation in HFD mice (approximately −30% less) compared to the TBStreated HFD mice (FIG. 1). In contrast, while all mice displayedincreases in muscle mass from baseline, there was no significantdifference among the treatment groups (FIG. 2).

Together, these data demonstrate that ALK7 mAbs can be used to reduceadipose levels in vivo. Therefore, the data indicate that ALK7antibodies may be useful in treating various disorders and complicationsassociated with undesirably high fat levels, particularly in obesepatients. Moreover, the show that fat reduction may be achieved withoutconcurrently increasing lean body mass, indicating that ALK7 Abs may beparticularly useful in treating patients where it is desirable to reducebody fat content without also increasing muscle mass.

What is claimed is:
 1. An activin receptor-Like Kinase 7 (ALK7)-bindingprotein comprising a heavy chain variable region (VH) comprising theamino acid sequence of SEQ ID NO: 117 and a light chain variable region(VL) comprising the amino acid sequence of SEQ ID NO: 124, wherein theprotein binds to ALK7.
 2. The ALK7-binding protein of claim 1, whereinthe ALK7-binding protein is an antibody, wherein the antibody is amonoclonal antibody, a recombinant antibody, a humanized antibody, achimeric antibody, a bi-specific antibody, a multi-specific antibody, oran ALK7-binding antibody fragment.
 3. The ALK7-binding protein of claim2, wherein the ALK7-binding antibody fragment is selected from the groupconsisting of a Fab fragment, a Fab′ fragment, a F(ab′)₂ fragment, a Fvfragment, a diabody, or a single chain antibody molecule.
 4. TheALK7-binding protein of claim 2, wherein the antibody further comprisesa heavy chain immunoglobulin constant domain selected from the groupconsisting of: (a) a human IgA constant domain; (b) a human IgD constantdomain; (c) a human IgE constant domain; (d) a human IgG1 constantdomain; (e) a human IgG2 constant domain; (f) a human IgG3 constantdomain; (g) a human IgG4 constant domain; and (h) a human IgM constantdomain.
 5. The ALK7-binding protein of claim 2, wherein the antibodyfurther comprises a light chain immunoglobulin constant domain selectedfrom the group consisting of: (a) a human Ig kappa constant domain; and(b) a human Ig lambda constant domain.
 6. The ALK7-binding protein ofclaim 2, wherein the antibody further comprises a human IgG1 heavy chainconstant domain and a human lambda light chain constant domain.
 7. AnALK7-binding protein comprising a set of CDRs in which: (i) VH-CDR1comprises the amino acid sequence of SEQ ID NO:114; (ii) VH-CDR2comprises the amino acid sequence of SEQ ID NO:115; (iii) VH-CDR3comprises the amino acid sequence of SEQ ID NO:116; (iv) VL-CDR1comprises the amino acid sequence of SEQ ID NO:121; (v) VL-CDR2comprises the amino acid sequence of SEQ ID NO:122; and (vi) VL-CDR3comprises the amino acid sequence of SEQ ID NO:123; wherein the proteinbinds ALK7.